Category Archive Autoimmune and Rare Diseases A – Z

Kallmann syndrome is a rare genetic condition where the brain does not make enough gonadotropin-releasing hormone (GnRH). Because of this, the body makes very low levels of the sex hormones (testosterone in males, oestrogen and progesterone in females). Puberty is delayed or does not happen, and fertility is usually reduced. At the same time, the person has a reduced or absent sense of smell (hyposmia or anosmia). This combination of low sex hormones and poor smell is the key feature of Kallmann syndrome. NCBI+1

Kallmann syndrome is a rare genetic condition where the brain does not release enough gonadotropin-releasing hormone (GnRH). This hormone normally tells the pituitary gland to make LH and FSH, which then stimulate the ovaries or testes to produce sex hormones. In Kallmann syndrome, this signal is weak or missing, so puberty is delayed or does not happen and fertility is reduced. Most people with Kallmann syndrome also have a very poor or absent sense of smell, because the nerve cells that should migrate to the brain in early development do not reach their normal place. NCBI+1

The problem in Kallmann syndrome starts very early in life, before birth. GnRH-producing nerve cells should move (migrate) from the area of the future nose (olfactory placode) into the hypothalamus in the brain. In Kallmann syndrome this movement is faulty, so the hypothalamus does not get enough GnRH neurons. As a result, the pituitary gland does not release luteinising hormone (LH) and follicle-stimulating hormone (FSH) properly, and the gonads (testes or ovaries) do not work normally. Wikipedia+1

Kallmann syndrome is one form of “congenital hypogonadotropic hypogonadism” (CHH). It is more common in males than females and is lifelong, but effective treatments can trigger puberty, maintain sexual health, protect the bones, and often improve fertility with specialist care. Orpha+1

Another names of Kallmann syndrome

Kallmann syndrome is known by several other names in medical books and articles. These names all describe the same basic problem of low sex hormones and poor sense of smell: Orpha+1

• Kallmann’s syndrome / Kallmann’s hereditary anosmia – older terms that highlight the link between the family history and loss of smell.

• Hypogonadotropic hypogonadism with anosmia – a descriptive name that means low gonadotropins (LH and FSH), low sex hormones, and no sense of smell.

• Congenital hypogonadotropic hypogonadism with anosmia (CHH with anosmia) – stresses that the condition is present from birth.

• Olfacto-genital dysplasia – older pathological term that focuses on problems in both the smell (olfactory) system and genital development.

• Isolated GnRH deficiency with anosmia – used in genetic and endocrine texts to stress that the primary problem is GnRH lack.

Types of Kallmann syndrome

Doctors and researchers group Kallmann syndrome into types based on the pattern of inheritance and the gene involved. Not every patient will fit neatly into one type, and in many people the exact gene is still unknown. Wikipedia+1

• X-linked Kallmann syndrome (ANOS1-related)
  This type is due to changes in the ANOS1 gene (formerly KAL1) on the X chromosome. It mainly affects males. Features can include Kallmann syndrome plus kidney absence on one side, mirror movements of the hands, and sometimes other birth defects.

• Autosomal dominant Kallmann syndrome (for example FGFR1, FGF8, CHD7, WDR11)
  In this pattern, a change in one copy of a gene (such as FGFR1 or FGF8) is enough to cause the condition. It can affect both males and females. Some genes cause extra features such as cleft lip or palate, dental problems, or heart defects.

• Autosomal recessive Kallmann syndrome (for example PROKR2, PROK2, TAC3, TACR3)
  Here, both copies of a gene must be changed to cause the disease. Parents are usually healthy carriers. This form can look similar clinically, with delayed puberty and poor smell, but may have slightly different associated features.

• Syndromic forms (overlap with other syndromes such as CHARGE, some MAB21L2 or CHD7 variants)
  In some people, Kallmann syndrome appears as part of a broader syndrome that includes eye, ear, heart, or other organ malformations. The hypogonadotropic hypogonadism and anosmia are then one part of a larger picture. Wikipedia+1

• Unknown-gene or sporadic cases
  Even with modern genetic panels, in many patients no disease-causing gene change is found. These people still have clear clinical Kallmann syndrome, and researchers think other genes or combined gene defects are involved. Wikipedia+1

Causes of Kallmann syndrome

Remember that Kallmann syndrome is almost always genetic and congenital. “Causes” here mainly means types of gene changes and inheritance patterns, plus factors that increase the chance of these changes being present or expressed. MedlinePlus+1

1. ANOS1 (KAL1) gene mutation
   Changes in the ANOS1 gene on the X chromosome are a classic cause of X-linked Kallmann syndrome. The gene helps guide GnRH and olfactory neurons as they migrate in the embryo. When it does not work properly, the neurons fail to reach the hypothalamus and olfactory bulbs, leading to low sex hormones and anosmia. Wikipedia

2. FGFR1 gene mutation
   FGFR1 encodes a receptor for fibroblast growth factor. Mutations disturb signalling needed for brain and olfactory development. This can cause autosomal dominant Kallmann syndrome, often with facial and skeletal anomalies such as cleft lip or palate. Wikipedia+1

3. FGF8 gene mutation
   FGF8 is a partner of FGFR1 in development. Changes in FGF8 can alter formation of the olfactory bulbs and GnRH neuron pathways, producing Kallmann syndrome or related hypogonadotropic hypogonadism. Wikipedia+1

4. PROKR2 gene mutation
   PROKR2 encodes a receptor involved in guiding neurons. Mutations can disrupt the route GnRH neurons take from the nasal region to the hypothalamus. Patients may have isolated Kallmann syndrome or combined features with other neurological signs. Wikipedia+1

5. PROK2 gene mutation
   PROK2 is the ligand for PROKR2. Genetic changes affecting this signalling pair can similarly block neuronal migration, leading to Kallmann syndrome with anosmia or hyposmia.

6. CHD7 gene mutation (CHARGE-overlap)
   CHD7 is classically linked to CHARGE syndrome, but milder variants can present mainly as Kallmann syndrome. The gene is important for early organ formation, including the olfactory system and hypothalamus. Wikipedia+1

7. WDR11 gene mutation
   WDR11 is another gene involved in normal brain development and GnRH neuron function. Mutations may lead to Kallmann syndrome or normosmic CHH with variable features such as craniofacial anomalies.

8. KISS1R (GPR54) gene mutation
   KISS1R helps control GnRH release. Changes in this gene can cause hypogonadotropic hypogonadism, and some people with such changes also have anosmia, fitting into the wider Kallmann spectrum. Wikipedia+1

9. GNRHR gene mutation
   GNRHR encodes the GnRH receptor on pituitary cells. Certain mutations reduce pituitary response to GnRH. Some families show both normosmic CHH and anosmic Kallmann-type cases, so GNRHR changes can contribute to the condition.

10. TAC3 gene mutation
    TAC3 encodes neurokinin B, a peptide that helps regulate GnRH neurons. Loss-of-function variants can cause severe GnRH deficiency and delayed puberty; a few reported patients also have smell defects. Medscape+1

11. TACR3 gene mutation
    TACR3 encodes the receptor for neurokinin B. Mutations disturb the signalling loop needed for GnRH neuron activity and can result in congenital hypogonadotropic hypogonadism with features overlapping Kallmann syndrome.

12. Other rare gene mutations (for example SEMA3A, HS6ST1, IL17RD)
    Several additional genes involved in axon guidance and brain development have been linked to Kallmann syndrome in small numbers of patients. Together they explain only part of the total genetic burden. Wikipedia+1

13. Digenic or oligogenic inheritance
    In some patients, changes in two or more genes at the same time appear to be required to produce the syndrome. This “oligogenic” pattern is an important modern concept and helps explain the wide range of severity seen in families. Wikipedia+1

14. De novo (new) gene mutation
    A child may develop Kallmann syndrome even when there is no family history. In these cases, a gene mutation appears for the first time in that child (de novo) in a sperm or egg cell or very early embryo.

15. Positive family history of Kallmann syndrome or CHH
    Having a close relative with Kallmann syndrome or congenital hypogonadotropic hypogonadism strongly increases the chance of carrying a related gene mutation, especially in X-linked or autosomal dominant forms. Orpha+1

16. Parental consanguinity (parents being related)
    When parents are related by blood, the chance that both are carriers of the same rare recessive mutation is higher. This can increase the risk of autosomal recessive Kallmann syndrome in their children.

17. Copy-number variants (small deletions or duplications of DNA)
    Some people with Kallmann syndrome have small pieces of DNA missing or duplicated around key genes. These structural changes can disrupt gene function even when the coding sequence looks normal.

18. Chromosomal rearrangements affecting key loci
    Rarely, balanced translocations or other chromosomal rearrangements can interrupt or move a gene important for GnRH neuron development, leading to a Kallmann-like picture.

19. Epigenetic changes affecting GnRH or olfactory genes
    Research suggests that abnormal epigenetic marks (like DNA methylation) might modify how certain genes are expressed, making symptoms worse or more likely when combined with genetic variants. ResearchGate

20. Unknown or yet-to-be-discovered genetic causes
    In many patients, careful testing still finds no mutation. This shows that there are still genes and mechanisms involved in GnRH neuron migration and smell development that science has not fully described yet. Wikipedia+1

Symptoms of Kallmann syndrome

People with Kallmann syndrome can have both reproductive and non-reproductive symptoms. Not everyone has all symptoms, and severity can differ even inside the same family. Orpha+1

1. Delayed or absent puberty
   One of the main signs is that puberty does not start on time, or progresses very slowly. Boys may not show voice change, facial hair, or testicular enlargement. Girls may not develop breasts or start periods by the expected age.

2. Poorly developed secondary sexual characteristics
   Even if some puberty changes occur, body hair, muscle bulk, breast size, or genital development may remain much less than is normal for age.

3. Primary amenorrhoea in females
   Girls and women with Kallmann syndrome often do not have their first menstrual period (primary amenorrhoea) because their ovaries are not being stimulated by LH and FSH. NCBI+1

4. Infertility or reduced fertility
   Without treatment, most adults with Kallmann syndrome cannot conceive children naturally, because sperm production in males and ovulation in females are severely reduced. Specialized hormone treatment can often improve fertility. NCBI+1

5. Micropenis in males
   Some boys are born with a very small penis, because they did not get the normal “mini-puberty” surge of testosterone in the first months of life.

6. Undescended testes (cryptorchidism)
   One or both testes may not move down into the scrotum before or soon after birth. This is a common early feature and a clue to possible GnRH deficiency. Wikipedia+1

7. Lack of sense of smell (anosmia) or reduced smell (hyposmia)
   Almost all people with classic Kallmann syndrome have a very poor or absent sense of smell. Many only notice this when tested, because smell loss can be subtle in daily life.

8. Cleft lip or cleft palate
   Some patients, especially those with FGFR1 or FGF8 mutations, have a split lip or roof of the mouth. This reflects a shared disturbance in midline facial development and brain development. Orpha+1

9. Dental problems or missing teeth (hypodontia)
   Some types of Kallmann syndrome are linked with missing or poorly formed teeth. This again shows a wider problem in tissue development, not only in the reproductive system.

10. Hearing problems
    Neural hearing loss can occur in some patients. They may have trouble hearing speech clearly, especially in noisy places, and may need hearing tests and aids. Wikipedia+1

11. Movement of both hands together (mirror movements / synkinesis)
    When the person moves one hand, the other hand may copy the movement involuntarily. This is especially associated with ANOS1-related X-linked Kallmann syndrome.

12. Abnormal hand or foot shape
    Some patients have “split hand/foot” (ectrodactyly), shortened fingers, or curved spine (scoliosis). These skeletal signs may help doctors suspect a specific gene cause. Wikipedia+1

13. Eye and eyelid problems
    There may be drooping eyelids (ptosis) or structural eye defects like coloboma in certain syndromic forms. These eye findings show that early embryonic development was disturbed in multiple areas.

14. Balance or coordination problems (ataxia)
    A few patients have poor balance or clumsy movements, suggesting involvement of parts of the brain that control coordination.

15. Low bone density and fractures (osteopenia or osteoporosis)
    Long-term lack of sex hormones leads to thin, fragile bones. Adults with untreated Kallmann syndrome have a higher risk of fractures and may need bone density tests and treatment. Wikipedia+1

Diagnostic tests

Physical exam

1. General growth and body-proportion exam
   The doctor checks height, weight, body mass index, and body proportions. Many people with Kallmann syndrome have normal height, but some may be slightly tall with long limbs because puberty was delayed and growth plates closed late. This exam also helps rule out other causes of delayed puberty such as chronic illness or malnutrition. NCBI+1

2. Examination of secondary sexual characteristics (Tanner staging)
   Tanner staging is a standard way to grade breast development in girls and genital and pubic hair development in boys and girls. In Kallmann syndrome, Tanner stage often remains low even in later teenage years, confirming delayed or absent puberty.

3. Genital examination in males
   The doctor inspects and gently examines the penis and scrotum. They check for micropenis, undescended testes, or very small testes, which are common in males with Kallmann syndrome. These findings support hypogonadism and make GnRH deficiency more likely. Wikipedia+1

4. Inspection for midline, skeletal, and facial defects
   The clinician looks for cleft lip or palate, missing or abnormal teeth, scoliosis, unusual hands or feet, and facial asymmetry. These clues can indicate specific gene types (such as FGFR1) and help guide genetic testing. Orpha+1

Manual tests

5. Bedside smell testing with common odours
   The doctor asks the patient to identify familiar smells such as coffee, mint, or soap while each nostril is tested separately. In Kallmann syndrome, the person usually cannot detect or recognise these smells. This simple test confirms anosmia or hyposmia in the clinic. MedlinePlus+1

6. Testicular volume measurement with an orchidometer
   In boys and men, a string of small plastic shapes (Prader orchidometer) is used to estimate testicular size by comparison. Testes smaller than about 4 mL after puberty age suggest hypogonadism and support a diagnosis of Kallmann syndrome or related CHH. NCBI+1

7. Neurologic bedside tests for balance and coordination
   Simple tests like walking in a straight line, standing with feet together and eyes closed, and touching finger to nose are used. Abnormal results may show cerebellar involvement or ataxia, which can occur in some syndromic forms of Kallmann syndrome.

8. Basic hearing screening (whisper test or tuning fork tests)
   The clinician may use a whispered voice or tuning fork to screen hearing in each ear. If problems are found, more detailed audiology tests are arranged. Neural hearing loss is a known associated feature in some patients. Wikipedia+1

 Lab and pathological tests

9. Serum LH and FSH levels
   A blood test measures luteinising hormone (LH) and follicle-stimulating hormone (FSH). In Kallmann syndrome, both are typically low or inappropriately normal despite low sex hormone levels. This pattern is the hallmark of hypogonadotropic hypogonadism. NCBI+1

10. Sex steroid levels (testosterone, oestradiol)
    Blood tests measure testosterone in males and oestradiol in females. In Kallmann syndrome, these levels are low for age and puberty stage. This supports the diagnosis and also helps to monitor hormone replacement treatment. NCBI+1

11. GnRH or GnRH-agonist stimulation test
    In specialised centres, synthetic GnRH or a GnRH agonist is given, and LH and FSH responses are measured. A poor or absent rise in these hormones reinforces the diagnosis of GnRH deficiency. This test can help distinguish Kallmann syndrome from simple constitutional delay of puberty in difficult cases. Medscape+1

12. Other pituitary hormone tests (TSH, prolactin, ACTH, GH, etc.)
    The doctor checks thyroid, cortisol, growth hormone, and prolactin levels to make sure the rest of the pituitary gland is working normally. This is important to exclude broader pituitary disease or brain tumours that can also cause delayed puberty. NCBI+1

13. Inhibin B and anti-Müllerian hormone (AMH)
    These markers reflect testicular or ovarian function. Low levels in a person with delayed puberty support gonadal under-function. They may help in distinguishing primary gonadal failure from central causes like Kallmann syndrome.

14. Genetic testing panel for Kallmann syndrome / CHH genes
    Modern gene panels can sequence many known Kallmann and CHH genes (such as ANOS1, FGFR1, PROKR2, CHD7 and others) at once. Finding a disease-causing variant confirms the diagnosis, helps guide family counselling, and may suggest associated anomalies to monitor. Wikipedia+1

15. Karyotype analysis
    A karyotype looks at the number and structure of chromosomes. It helps separate Kallmann syndrome from other conditions that also cause hypogonadism, such as Klinefelter syndrome (47,XXY) or Turner syndrome (45,X). In Kallmann syndrome, the karyotype is usually normal. Medscape+1

Electrodiagnostic tests

16. Olfactory evoked potentials
    This specialised test records electrical activity in the brain when the nose is stimulated with odours. In Kallmann syndrome, responses are often absent or greatly reduced, confirming a problem in the smell pathway. It is especially useful in research or complex diagnostic cases. ScienceDirect+1

17. Brainstem auditory evoked responses (BAER)
    If hearing problems are suspected, BAER tests measure the brain’s electrical reaction to sound clicks. Abnormal results indicate neural hearing impairment, which can be part of some syndromic forms of Kallmann syndrome.

Imaging tests

18. MRI of the brain and pituitary with focus on olfactory bulbs
    Magnetic resonance imaging (MRI) is the key imaging test. It can show small or absent olfactory bulbs and tracts, which strongly supports Kallmann syndrome. MRI also checks the hypothalamus and pituitary to exclude tumours or structural lesions that might cause similar hormone problems. NCBI+1

19. Ultrasound of testes and kidneys
    Ultrasound can measure testicular size, look for undescended testes, and identify kidney abnormalities such as absence of one kidney (unilateral renal agenesis), which is common in ANOS1-related cases. This helps characterise the full extent of the syndrome in each person. Wikipedia+1

20. Bone mineral density scan (DEXA)
    A dual-energy X-ray absorptiometry (DEXA) scan measures bone density. Adults with long-standing untreated Kallmann syndrome often show osteopenia or osteoporosis because of years with low sex hormone levels. Detecting this early allows doctors to start treatment to strengthen bones and prevent fractures. Wikipedia+1

Non-Pharmacological Treatments (Therapies and Other Approaches)

1. Puberty and disease education
   A clear explanation of Kallmann syndrome, puberty and fertility helps the patient and family understand why puberty is delayed and what treatment can do. Simple education reduces fear and shame, improves treatment adherence and makes it easier to talk about body changes, sex, and future pregnancy. Knowing that hormone replacement can build bones and sexual characteristics helps people accept long-term care and screening for complications such as osteoporosis and infertility. NCBI+1

2. Psychological counselling or cognitive-behavioural therapy (CBT)
   Delayed puberty, short stature, and lack of sexual development can cause low self-esteem, anxiety, depression, and social withdrawal. Talking therapy, including CBT, helps patients reframe negative thoughts about their body, cope with teasing, and learn social skills. Good mental health support improves quality of life, supports treatment adherence and reduces the risk of self-stigma that often appears in people with chronic conditions and disorders of sexual development. PMC+1

3. Sexual health and relationship counselling
   People with Kallmann syndrome may feel inexperienced or embarrassed about sexual activity because puberty started late or never started without treatment. Sex counselling gives simple information on consent, safe sex, contraception, pleasure, and ways to talk with partners about the condition. This support helps build confidence, improves intimate relationships and reduces anxiety about fertility and body image. OUP Academic+1

4. Genetic counselling and family planning support
   Kallmann syndrome is often genetic, with several known genes involved. Genetic counselling explains inheritance patterns, recurrence risk for future children, and options such as genetic testing for family members or prenatal counselling. This helps families make informed decisions about pregnancy and screening and reduces guilt or blame between parents and children. PMC+1

5. Fertility counselling and assisted-reproduction planning
   Fertility can often be restored with proper hormone and gonadotropin treatment, but this may take months or years. Fertility counselling explains how sperm or egg production can be induced, what success rates look like, and when assisted reproductive techniques such as IVF or ICSI might be needed. Planning ahead reduces stress, helps patients time pregnancies with work or study, and encourages sperm or oocyte banking when fertility is achieved. Annals of Translational Medicine+1

6. Bone-health lifestyle program (exercise, posture, fall prevention)
   Long-standing hypogonadism can reduce bone mineral density and increase fracture risk. A structured plan that includes regular weight-bearing and resistance exercise, balance training, and posture work helps strengthen bones and muscles. Combined with calcium and vitamin D intake, this non-drug approach can improve bone strength and reduce fracture risk in men and women with hypogonadism. PMC+2OUP Academic+2

7. Nutrition counselling for bone and metabolic health
   Dietitians can design meal plans rich in calcium (dairy, leafy greens), vitamin D (fortified foods, oily fish), magnesium and protein to support healthy bones and muscle mass. They also address weight control, blood pressure, cholesterol and blood sugar, because low sex hormones can worsen cardiometabolic risk. A stable, balanced diet supports overall health and may improve energy and mood. Office of Dietary Supplements+2Bone Health & Osteoporosis Foundation+2

8. Structured physical activity program
   Regular moderate exercise such as brisk walking, cycling or swimming improves fitness, mood, insulin sensitivity and cardiovascular risk in patients with hypogonadism. Strength training adds extra benefits for bone density and muscle mass. A supervised plan with gradual progression makes exercise safe even for people with low fitness or previous fractures. OUP Academic+1

9. Sleep hygiene and fatigue management
   Hormone imbalances, mood symptoms and low fitness can disturb sleep. Simple steps such as regular bedtimes, limiting screens before bed, relaxing routines and limiting caffeine can improve sleep quality. Good sleep supports hormone balance, mood, weight control and daytime functioning, making it easier to cope with chronic disease and follow complex treatment schedules. OUP Academic+1

10. Smell-safety strategies for anosmia
    Because most people with Kallmann syndrome cannot smell, they may not notice smoke, gas leaks, spoiled food or body odour. Practical safety measures include smoke and gas detectors, date-labelling food, asking others to check for gas leaks and checking expiry dates regularly. These strategies reduce the risk of poisoning, foodborne illness and household accidents that people with a normal sense of smell might naturally avoid. Wikipedia+1

11. Olfactory training (if any residual smell)
    Some patients have reduced, not totally absent, smell. In these cases, smell training using repeated exposure to a set of odours (for example rose, lemon, cloves and eucalyptus) may slightly improve olfactory function, based on data from other forms of smell loss. The mechanism likely involves neuroplasticity and repeated stimulation of remaining olfactory neurons. Even small improvements may help with food enjoyment and safety. PMC+1

12. Educational and workplace support
    Delayed puberty and shorter height may lead to bullying or academic problems. School or university accommodations, career counselling and flexible schedules for clinic visits can protect educational progress. In adults, disclosure support and reasonable adjustments at work help people manage frequent appointments, fertility treatments and occasional fatigue, reducing stress and improving long-term job stability. PMC+1

13. Peer and patient-support groups
    Connecting with others who have Kallmann syndrome or congenital hypogonadotropic hypogonadism reduces isolation and shame. Online or local support groups allow people to share practical tips about injections, fertility journeys, relationships and mental health. Peer support often increases hope and resilience, helping patients stay engaged with long-term hormone replacement. PMC+1

14. Family and partner education sessions
    When parents, siblings or partners better understand Kallmann syndrome, they can offer emotional and practical support rather than pressure or blame. Joint education visits show relatives why puberty was delayed, why fertility treatment can take time, and why lifelong follow-up is important. This reduces conflict around treatment adherence and fertility decisions. PMC+1

15. Structured follow-up and monitoring program
    Regular review with an endocrinologist or reproductive specialist allows stepwise hormone dose increases during puberty induction, adjustment of adult maintenance doses, and monitoring of bone density and blood tests. Structured follow-up prevents overtreatment, under-treatment and missed complications such as osteoporosis, metabolic syndrome or polycythaemia from high doses of testosterone. OUP Academic+1

16. Management of associated anomalies (kidney, hearing, craniofacial)
    Some patients have associated problems such as one missing kidney, hearing loss, cleft lip/palate or limb defects. Care from nephrology, ENT, audiology, and craniofacial teams can protect kidney function, improve hearing and speech, and correct physical problems that affect feeding or appearance. Addressing these associated conditions is part of holistic Kallmann syndrome management. NCBI+1

17. Fall-prevention and fracture-risk assessment
    If bone density is low, a falls-prevention plan (home safety checks, balance training, vision correction and proper footwear) further reduces fracture risk. Screening tools and bone-density tests guide the intensity of lifestyle and drug therapy. Preventing the first fracture is especially important, because previous fractures predict future ones. PMC+2Wiley Online Library+2

18. Cardiometabolic risk management (non-drug)
    Low sex hormones may worsen abdominal fat, lipids and insulin resistance. Lifestyle measures such as healthy diet, exercise, weight control and smoking cessation reduce long-term risks of heart attack and stroke. These steps complement hormone therapy and, when successful, may reduce the need for multiple medicines for blood pressure, cholesterol or diabetes later in life. PMC+2JACC+2

19. Digital reminders and self-management tools
    Smartphone apps, alarms or calendars help patients remember injections, patches, blood tests and clinic visits. Tracking symptoms (mood, energy, libido, periods, erections) alongside treatment doses allows doctor and patient to fine-tune therapy together. Better self-management is linked with better outcomes in many chronic endocrine diseases. OUP Academic+1

20. Healthy lifestyle for general immunity
    Balanced diet, regular physical activity, enough sleep, stress management and up-to-date vaccines (influenza, COVID-19 and others recommended locally) support general immune function. Although these measures do not “cure” Kallmann syndrome, they lower the risk of infections, help protect bones and heart and improve overall quality of life. Office of Dietary Supplements+2Healthy Bones Australia+2

Drug Treatments

Important: Exact drug choice, dose and schedule must always be decided by an endocrinologist or reproductive specialist, after individual assessment. Information below is general and based on FDA labels and endocrine guidelines, not a prescription for any specific person.

1. Testosterone cypionate injection
   Testosterone cypionate is a long-acting injectable androgen used for testosterone-replacement therapy in males with confirmed hypogonadism, including selected cases of hypogonadotropic hypogonadism. Typical doses for adults are 50–400 mg intramuscularly every 2–4 weeks, adjusted to keep testosterone in the normal range and avoid side effects such as acne, high red blood cell count, sleep apnoea or fluid retention. It helps develop male secondary sexual characteristics, increase muscle and bone mass and improve libido and energy. FDA Access Data+3FDA Access Data+3FDA Access Data+3

2. Other injectable testosterone esters (e.g., testosterone enanthate)
   Injectable testosterone esters are widely used for male puberty induction and lifelong replacement when fertility is not currently desired. Doses are usually started low and increased over months to mimic natural puberty, then stabilised for adult maintenance. The mechanism is direct replacement of missing testosterone, which supports genital growth, hair growth, voice deepening and normal bone mineralisation. Monitoring includes blood counts, lipids, liver enzymes and PSA in older men to detect adverse effects early. Medscape+2EMRO Dashboards+2

3. Transdermal testosterone gel
   Testosterone gel is applied daily to clean, dry skin on the shoulders, upper arms or abdomen. It provides more stable testosterone levels compared with intermittent injections and may be preferred in adults once puberty is complete. The gel’s mechanism is the same hormone replacement, but absorption through the skin allows finer dose adjustments. Patients must avoid skin-to-skin transfer to others, especially women and children, and report side effects such as acne, mood changes or high red blood cell counts. Medscape+1

4. Transdermal testosterone patch
   Testosterone patches deliver controlled testosterone through the skin, usually applied once daily. They are helpful for men who dislike injections or have variable responses to gels. The purpose is to restore testosterone levels, improve sexual function and maintain bone and muscle mass. Skin irritation at the patch site is the most common side effect, so rotation of sites and skin care are important. Medscape+1

5. Estradiol (oral or transdermal) for females
   In girls and women with Kallmann syndrome, estradiol is introduced in low doses and slowly increased to mimic natural puberty. Later, a progestin is added to create menstrual cycles and protect the uterine lining. Estradiol improves breast development, uterine growth, bone density and cardiovascular health. Patches often provide steadier hormone levels and may have a lower risk of clotting than some oral preparations, though this depends on the individual. OUP Academic+2Cleveland Clinic+2

6. Estrogen–progestin combined therapy (including some oral contraceptives)
   Once puberty is established, many women move to a combined estrogen–progestin pill, patch or ring. These medicines provide cyclic bleeding or amenorrhoea, protect the uterine lining and give reliable contraception if pregnancy is not yet desired. They work by replacing ovarian hormones and, in contraceptive doses, suppressing ovulation. Risks include blood clots, hypertension and migraines in susceptible women, so careful screening is essential. OUP Academic+1

7. Pulsatile GnRH therapy (gonadorelin via pump)
   In some centres, a small pump delivers GnRH under the skin every 60–90 minutes, mimicking natural pulses from the hypothalamus. This can induce puberty and restore fertility in selected patients with hypothalamic GnRH deficiency. Studies in congenital hypogonadotropic hypogonadism show that pulsatile GnRH can induce spermatogenesis and ovulation with good safety when carefully monitored. The main drawbacks are cost, need for specialised centres and pump management. PubMed+4Annals of Translational Medicine+4Fertstert+4

8. Human chorionic gonadotropin (hCG) injection
   hCG acts like LH and stimulates Leydig cells in the testes to produce testosterone. FDA-approved hCG products such as Pregnyl and Novarel are indicated for selected cases of hypogonadotropic hypogonadism and infertility. Typical regimens for men involve subcutaneous or intramuscular injections several times per week, often combined later with FSH to start sperm production. Side effects include breast tenderness, mood changes, acne and risk of gynaecomastia. FDA Access Data+4FDA Access Data+4FDA Access Data+4

9. FSH (follitropin alfa, e.g., GONAL-F, GONAL-F RFF)
   Recombinant FSH stimulates Sertoli cells in the testes or follicles in the ovaries. In men with hypogonadotropic hypogonadism, FSH is used with hCG to induce spermatogenesis. In women, FSH is part of controlled ovarian stimulation. FDA labels for GONAL-F describe its indications for induction of spermatogenesis and ovulation, with careful monitoring to avoid ovarian hyperstimulation in women. Side effects can include injection-site reactions, ovarian enlargement and multiple pregnancies in women. FDA Access Data+3FDA Access Data+3FDA Access Data+3

10. FSH (follitropin beta, Follistim AQ)
    Follistim AQ (follitropin beta) is another recombinant FSH preparation indicated for induction of spermatogenesis in men with hypogonadotropic hypogonadism and for ovulation induction in women. The mechanism is the same as other FSH products: stimulation of follicles or seminiferous tubules. Men receive it with hCG after a period of hCG alone, and treatment can last many months. Monitoring sperm counts, testicular volume and hormone levels guides dosage. FDA Access Data+1

11. Human menopausal gonadotropin (hMG, menotropins)
    hMG preparations contain both FSH and LH activity from urinary sources. They are used in some fertility protocols for women and occasionally in men. For Kallmann syndrome, hMG may help induce ovulation or support spermatogenesis where recombinant products are not available. Because hMG is potent, ultrasound and hormone monitoring are vital to reduce risks such as ovarian hyperstimulation and multiple pregnancy. Annals of Translational Medicine+2Synapse+2

12. Clomiphene citrate
    Clomiphene is a selective estrogen receptor modulator that blocks estrogen feedback at the hypothalamus and pituitary, increasing endogenous gonadotropin release. It is mainly used to induce ovulation in women with an intact hypothalamic–pituitary axis, and sometimes in men with functional hypogonadism. In classic Kallmann syndrome, where GnRH neurons are absent, its effect is limited, but it may be useful in milder or overlapping forms of hypogonadotropic hypogonadism. Side effects include hot flashes, mood changes and visual symptoms. OUP Academic+1

13. Aromatase inhibitors (e.g., letrozole)
    Letrozole reduces estrogen production, which can increase FSH secretion and induce ovulation in certain women with ovulatory disorders. It is used in infertility treatment, often when clomiphene is ineffective. In true Kallmann syndrome, it has limited role without adequate GnRH drive, but may be used in related infertility conditions. Side effects can include hot flashes, joint pain and headaches. OUP Academic+1

14. High-dose vitamin D (prescription strength) when deficient
    Many people with hypogonadism have low vitamin D, which worsens bone health. Prescription vitamin D2 or D3 (e.g., 50,000 IU weekly for a limited period) may be used to correct deficiency, followed by maintenance doses (often 800–1000 IU/day for adults, adjusted to blood levels). Vitamin D improves calcium absorption and bone mineralisation but can cause toxicity if excessively dosed, so blood monitoring is essential. theros.org.uk+3Office of Dietary Supplements+3Bone Health & Osteoporosis Foundation+3

15. Calcium supplements when intake is low
    If dietary calcium is insufficient, calcium carbonate or citrate supplements may be recommended to reach daily targets, often 1000–1200 mg/day from food plus supplements. Adequate calcium, together with vitamin D and sex-hormone replacement, is crucial to maintain bone density in hypogonadal individuals and reduce fracture risk. Excess calcium may cause kidney stones or constipation, so dosing should be individualised. PMC+2Bone Health & Osteoporosis Foundation+2

16. Bisphosphonates (e.g., alendronate) for osteoporosis
    In patients with Kallmann syndrome who already have osteoporosis or fragility fractures despite hormone replacement, bisphosphonates can be considered. These drugs reduce bone resorption by inhibiting osteoclasts, increasing bone mineral density and lowering fracture risk. They are taken orally or intravenously, typically weekly or yearly depending on the formulation. Side effects include gastrointestinal irritation and, rarely, osteonecrosis of the jaw, so dental checks and correct administration are important. EMRO Dashboards+2ScienceDirect+2

17. Teriparatide (parathyroid hormone analog)
    Teriparatide is an anabolic osteoporosis drug that stimulates new bone formation and is indicated for men and women at very high fracture risk, including those with hypogonadal osteoporosis. It is given as a daily subcutaneous injection of 20 µg for up to two years. It works by activating osteoblasts more than osteoclasts. Because of cost and potential risks, including hypercalcaemia and rare concerns about osteosarcoma in animal studies, it is reserved for severe cases. FDA Access Data+3FDA Access Data+3FDA Access Data+3

18. Denosumab
    Denosumab is a monoclonal antibody against RANKL used for patients with high fracture risk who cannot take other osteoporosis medicines. It is given as a subcutaneous injection every six months and strongly reduces bone resorption. It may be considered in severe hypogonadal osteoporosis under specialist care. Side effects can include low calcium, infections and rare jaw osteonecrosis, so monitoring calcium and dental health is essential. FDA Access Data+3FDA Access Data+3FDA Access Data+3

19. Romosozumab (EVENITY)
    Romosozumab is a sclerostin-inhibiting monoclonal antibody used for a limited 12-month course in postmenopausal women at very high fracture risk. It increases bone formation and decreases bone resorption. It is not specific to Kallmann syndrome but may be used in rare cases with severe osteoporosis under strict cardiology and endocrine supervision due to possible cardiovascular risks. FDA Access Data+3FDA Access Data+3FDA Access Data+3

20. Other supportive medicines (e.g., lipid- or blood-pressure-lowering drugs)
    Because long-term hypogonadism can worsen cardiovascular risk, some patients may also need statins, antihypertensives or diabetes medicines. These drugs do not treat Kallmann syndrome itself but reduce long-term risks of heart disease and stroke. Their use must be based on standard cardiovascular-risk algorithms, not solely on the diagnosis of Kallmann syndrome. PMC+2JACC+2

Dietary Molecular Supplements

Supplements should only be used under medical supervision, especially in teenagers, pregnant women, and people with kidney or liver disease.

1. Vitamin D3
   Vitamin D3 supports calcium absorption, bone mineralisation, muscle function and immune modulation. Many adults need around 600–1000 IU daily, though doses must be adjusted based on blood levels and sunlight exposure. In Kallmann syndrome, adequate vitamin D is particularly important because of increased osteoporosis risk. Too much vitamin D can cause high calcium, kidney problems and heart rhythm disturbances, so self-prescribing high doses is unsafe. theros.org.uk+3Office of Dietary Supplements+3Bone Health & Osteoporosis Foundation+3

2. Calcium
   If dietary calcium intake is low, supplements can help reach the usual adult target of about 1000–1200 mg per day from all sources. Calcium is a key building block of bone, and its effect is strongest when combined with vitamin D and adequate sex-hormone replacement. Excess intake, especially with high vitamin D, may increase risk of kidney stones or vascular calcification, so dosing should follow professional advice. PMC+2Bone Health & Osteoporosis Foundation+2

3. Omega-3 fatty acids (fish-oil or algae-oil)
   Omega-3 fatty acids (EPA and DHA) do not treat Kallmann syndrome directly, but they support heart and blood-vessel health, which is important because hypogonadism can worsen cardiometabolic risk. Typical supplemental doses range from about 250–500 mg EPA+DHA daily, adjusted for individual needs. Omega-3s help lower triglycerides and inflammation and may slightly reduce cardiovascular events in high-risk patients. Harvard Health+3PMC+3AHA Journals+3

4. Zinc
   Zinc is important for normal testicular function, sperm production and immune health. Severe zinc deficiency is linked to hypogonadism, and clinical studies show that zinc supplementation can improve outcomes in some men with hypogonadotropic hypogonadism. A common medical dose is around 50 mg elemental zinc once or twice daily for a limited period, but long-term high doses can cause copper deficiency and other problems, so monitoring is needed. ScienceDirect+3PubMed+3Taylor & Francis Online+3

5. Magnesium
   Magnesium supports vitamin D activation, muscle function and energy production. Low magnesium can worsen cramps, fatigue and bone health. Doses of 200–400 mg/day from diet and supplements are often used, adjusted to kidney function and bowel tolerance. Magnesium does not treat Kallmann syndrome itself but helps optimise bone and muscle health, especially in people taking vitamin D and calcium. EatingWell+1

6. Vitamin K2
   Vitamin K2 helps direct calcium into bone and away from blood vessels by activating osteocalcin and matrix Gla protein. Some observational and interventional studies suggest that vitamin K2 may improve bone density and reduce fractures when combined with calcium and vitamin D, though evidence is less robust than for vitamin D. Typical supplement doses vary by preparation and should follow product and professional guidance. PMC+2Healthy Bones Australia+2

7. B-complex vitamins
   B vitamins support energy metabolism, nerve function and red-blood-cell production. In people with fatigue, poor diet or heavy medication use, a B-complex can correct subtle deficiencies. While they do not change GnRH or sex-hormone levels, they may improve overall wellbeing and support a healthy nervous system. Doses vary by product; high doses of some B vitamins can cause side effects, so balance is important. Office of Dietary Supplements+1

8. Iron (only if deficient)
   Iron supplements are used to treat iron-deficiency anaemia, which can cause fatigue, breathlessness and poor exercise tolerance. Anaemia is not specific to Kallmann syndrome but may coexist. Typical doses range from 30–100 mg elemental iron per day under medical supervision. Excess iron can damage organs, so supplementation is only appropriate after blood tests show deficiency. Office of Dietary Supplements+1

9. Protein and amino-acid supplements
   Adequate protein supports muscle growth and bone structure, especially when hormone replacement and exercise are started. For people who struggle to meet protein needs through food (for example due to low appetite or restrictive diets), whey or plant-protein powders can help. General adult targets are around 1.0–1.2 g/kg/day in many bone-health guidelines, with adjustments for kidney function and age. OUP Academic+1

10. Multivitamin tailored to bone and metabolic health
    A well-designed multivitamin–mineral supplement may help cover small dietary gaps in people with Kallmann syndrome, especially if appetite or food variety is low. Products that include vitamin D, calcium, magnesium, zinc and B vitamins can complement, but not replace, a healthy diet and hormone therapy. Choice and dosing should be individualised; megadose multivitamins are unnecessary and may be harmful. Office of Dietary Supplements+2Bone Health & Osteoporosis Foundation+2

Immunity-Booster and Regenerative / Stem-Cell Drugs

At present, there are no FDA-approved stem-cell or regenerative drugs that cure Kallmann syndrome or directly replace the missing GnRH-producing neurons. Current research uses stem-cell models to understand the disease and test ideas in the lab, but these are not ready as treatments in patients. PMC+2Nature+2

Some drugs described above (teriparatide, romosozumab, denosumab) are “bone-active” and help repair or preserve skeletal tissue in people with severe osteoporosis, but they do not fix the underlying genetic cause of Kallmann syndrome and are not general immune boosters. FDA Access Data+4FDA Access Data+4FDA Access Data+4

For immunity, the most evidence-based “treatments” are lifestyle steps (sleep, nutrition, exercise) and recommended vaccinations, not special immune-booster drugs. Any claim of stem-cell “cure” or miracle immune drug for Kallmann syndrome outside a regulated clinical trial should be viewed with extreme caution. Swiss Medica+2Office of Dietary Supplements+2

Surgeries Used in or Around Kallmann Syndrome

1. Orchidopexy for undescended testes
   Some males with Kallmann syndrome have undescended testes. Orchidopexy is the surgical procedure that moves the testis into the scrotum and fixes it there. It is usually done in childhood to improve fertility potential, allow easier examination for cancer and reduce torsion risk. In Kallmann syndrome, even after orchidopexy, hormonal treatment is still needed for puberty and fertility. NCBI+1

2. Cleft lip and palate repair
   A minority of patients may have craniofacial anomalies, including cleft lip or palate. Surgical repair in childhood improves feeding, speech, facial appearance and psychosocial functioning. Correcting these structural problems does not affect the hormonal defect but significantly improves quality of life and social integration. NCBI+2PMC+2

3. Ear, nose and throat (ENT) surgery for associated anomalies
   Some patients have ear or nasal structural problems, such as nasal obstruction or chronic sinus disease, which may worsen breathing and sleep quality. ENT surgery (septoplasty, sinus surgery, ear procedures) can improve airflow, hearing and comfort. While these procedures do not restore the lost olfactory neurons characteristic of Kallmann syndrome, they treat co-existing anatomical issues. NCBI+1

4. Testicular sperm extraction (TESE / micro-TESE) with ART
   In severe male infertility, even after long-term hCG/FSH therapy, sperm may be very low. In such cases, urologists may surgically retrieve sperm directly from the testes using TESE or micro-TESE. The retrieved sperm can be used in IVF/ICSI cycles. This procedure is used only in specialised fertility centres after detailed hormonal and genetic evaluation. OUP Academic+2SpringerLink+2

5. Fracture fixation or spine surgery for osteoporotic fractures
   If untreated hypogonadism leads to severe osteoporosis, patients may suffer vertebral or other bone fractures. Orthopaedic surgery may then be needed to stabilise fractures, relieve pain or correct deformity. While this surgery is not specific to Kallmann syndrome, it is a serious downstream consequence of long-standing low sex-hormone levels and illustrates why early diagnosis and bone protection are so important. PMC+2Wiley Online Library+2

Prevention

Kallmann syndrome itself, being genetic, cannot currently be prevented, but many complications can:

1. Early diagnosis and referral to an endocrinologist – noticing absent puberty, no menstruation by about 15–16, or lack of testicular enlargement and seeking specialist care early protects bones and fertility. NCBI+1

2. Timely puberty induction and hormone replacement – starting sex-hormone therapy at the appropriate age supports normal growth, bone mass and psychosocial development, reducing long-term complications. OUP Academic+2PMC+2

3. Regular bone-density monitoring and treatment – DEXA scans and early calcium/vitamin D and, where needed, osteoporosis medicines help prevent fractures. PMC+2MaplesPub+2

4. Healthy weight, diet and exercise – maintaining a healthy BMI, eating a nutrient-dense diet and exercising regularly reduces cardiovascular and metabolic risk. PMC+2JACC+2

5. Smoking cessation and limiting alcohol – avoiding smoking and heavy alcohol helps protect bones, heart and fertility. PMC+2Wiley Online Library+2

6. Adherence to hormone and fertility treatment – following the plan for injections, patches and monitoring prevents under-treatment and reduces risks from excessive doses. OUP Academic+2Medscape+2

7. Managing associated anomalies (kidney, hearing, craniofacial) – early detection and targeted treatment reduce long-term organ damage and disability. NCBI+1

8. Vaccinations and infection prevention – recommended vaccines protect general health, especially for those with fractures, surgeries or chronic therapy. Office of Dietary Supplements+1

9. Mental-health support – early counselling and support for mood or anxiety problems reduces the risk of long-term psychiatric complications. PMC+1

10. Genetic counselling for future pregnancies – families can understand recurrence risks and consider testing or early monitoring in future children. PMC+1

When to See a Doctor

You (or a child) should see a doctor, preferably an endocrinologist, if:

• Puberty has not started by about age 13 in girls or 14 in boys, or there is very slow progression of pubertal changes. NCBI+1

• Periods have not started by age 15–16, or periods stop for many months without pregnancy. NCBI+1

• Testes remain very small, penis growth is poor, or there is no facial and body hair development in a teenage boy. NCBI+1

• There is a lifelong inability to smell (anosmia) together with delayed puberty or infertility. NCBI+1

• There is difficulty conceiving after 12 months of trying (or earlier if periods are absent or male puberty was abnormal). OUP Academic+1

• There are unexplained fractures, back pain, height loss or strong suspicion of osteoporosis. PMC+1

Any new severe symptom such as chest pain, shortness of breath, sudden leg swelling, vision changes, severe headache or neurological symptoms during hormone or bone-active therapy requires urgent medical attention, as these may signal rare but serious drug side effects. FDA Access Data+3FDA Access Data+3FDA Access Data+3

What to Eat and What to Avoid

1. Calcium-rich foods vs. very low-calcium diets
   Eat dairy (milk, yoghurt, cheese), calcium-fortified plant milks, tofu, and leafy greens to support bones. Avoid long-term very low-calcium or fad diets that exclude whole food groups without medical advice. PMC+2Bone Health & Osteoporosis Foundation+2

2. Vitamin-D-rich foods vs. ignoring deficiency
   Include oily fish, egg yolks and fortified foods. If sun exposure is low, discuss supplements. Do not ignore confirmed vitamin D deficiency, and do not self-prescribe megadoses above safe limits. Office of Dietary Supplements+2osteoporosis.foundation+2

3. Lean proteins vs. ultra-processed high-salt meats
   Eat lean poultry, fish, eggs, beans, lentils and nuts to support muscle and bone. Limit processed meats and very salty snacks, which may harm blood pressure and overall health. OUP Academic+1

4. Whole grains and fibre vs. refined sugars
   Choose whole-grain bread, brown rice and oats, plus fruit and vegetables, to keep blood sugar and weight stable. Avoid large amounts of sugary drinks and sweets that increase diabetes and heart-disease risk. PMC+1

5. Healthy fats vs. trans fats and deep-fried foods
   Include sources of healthy fats such as olive oil, nuts, seeds and oily fish. Limit trans-fat-rich snacks and frequent deep-fried fast food, which worsen cholesterol and cardiovascular risk. PMC+2AHA Journals+2

6. Plenty of fruit and vegetables vs. very restrictive diets
   Aim for a colourful variety of fruit and vegetables every day to provide vitamins, minerals and antioxidants that support bone, heart and immune health. Avoid extreme “detox” or starvation diets that can worsen bone loss and fatigue. EatingWell+1

7. Adequate fluids vs. sugary and energy drinks
   Drink water regularly throughout the day. Minimise sugar-sweetened drinks and high-caffeine energy drinks that can affect sleep, weight and heart health. PMC+1

8. Moderate caffeine vs. heavy caffeine use
   Small to moderate amounts of coffee or tea are usually fine, but very high intake can disturb sleep, raise heart rate and reduce calcium absorption slightly. Balance is important, especially when bone health is already fragile. PMC+1

9. Limited alcohol vs. regular heavy drinking
   If you drink alcohol and it is legal and safe for your age, keep intake low. Heavy alcohol use damages bone, liver and hormonal balance and raises accident risk, especially with osteoporosis. PMC+1

10. No smoking vs. any smoking
    The best choice for bone and heart health is not to smoke at all. Smoking worsens osteoporosis and cardiovascular disease and interferes with fertility. PMC+2Wiley Online Library+2

Frequently Asked Questions (FAQs)

1. Can Kallmann syndrome be cured?
   Right now there is no cure that restores normal GnRH neurons, so Kallmann syndrome is usually lifelong. However, hormone replacement and fertility treatments can give normal pubertal development, strong bones and a good chance of having children. SpringerLink+3NCBI+3OUP Academic+3

2. Will I ever go through puberty?
   With the right hormone treatment, most people with Kallmann syndrome can develop breasts, periods, facial hair, deeper voice, and other pubertal changes. Doctors usually start with low doses and increase slowly to mimic natural puberty. OUP Academic+2Medscape+2

3. Can I have children if I have Kallmann syndrome?
   Many men and women with Kallmann syndrome can have biological children using gonadotropin or GnRH therapy, often combined with assisted reproductive techniques. Treatment can be long and needs specialist care, but success rates are encouraging in experienced centres. Annals of Translational Medicine+2SpringerLink+2

4. Why is my sense of smell affected?
   In Kallmann syndrome, the cells that become GnRH neurons and olfactory neurons fail to migrate properly during early development. This leads to both hormonal deficiency and reduced or absent smell. Smell usually does not fully return even with treatment. NCBI+2Wikipedia+2

5. Is Kallmann syndrome inherited?
   Yes, it is often genetic, with different inheritance patterns (X-linked, autosomal dominant or recessive, and others). Genetic testing and counselling can help clarify the specific pattern in a family and guide screening of relatives. PMC+1

6. Why do doctors worry about my bones?
   Low sex-hormone levels over many years lead to low bone mineral density and fractures. That is why doctors emphasise early hormone treatment, vitamin D, calcium, exercise and sometimes bone-specific drugs like bisphosphonates or teriparatide. PMC+2Wiley Online Library+2

7. Do I have to take hormones for life?
   Most people need long-term hormone replacement to maintain sexual characteristics, bone health and wellbeing. Rarely, some people experience partial “reversal” of hypogonadotropic hypogonadism, but this is unpredictable and can relapse, so it must never be assumed without careful medical testing. SpringerLink+2PMC+2

8. Are there serious risks from testosterone or estrogen treatment?
   All hormones have potential risks, such as clotting, high red blood cells, blood-pressure changes or mood changes, especially at high doses or in older patients. Careful dosing, regular blood tests and monitoring by an experienced clinician keep risks as low as possible while providing strong benefits. FDA Access Data+2FDA Access Data+2

9. Can diet or supplements replace hormone treatment?
   No. Diet, vitamin D, calcium and other supplements support general health but cannot replace sex hormones. Without hormone replacement, puberty will not fully occur, and bone and fertility problems will persist. MaplesPub+3OUP Academic+3PMC+3

10. Is stem-cell therapy available for Kallmann syndrome?
    At present, stem-cell approaches for Kallmann syndrome are only in laboratory research models and not approved for clinical treatment. Any clinic claiming to cure Kallmann syndrome with stem cells should be viewed with extreme caution. Swiss Medica+3Nature+3PMC+3

11. Why do I need mental-health support?
    Living with delayed puberty, infertility or chronic treatment can be emotionally hard. Depression, anxiety and body-image problems are common. Psychological support and peer groups can greatly improve quality of life and coping skills. PMC+1

12. Can Kallmann syndrome affect other organs?
    Yes, some patients have missing kidney, hearing loss, craniofacial anomalies, limb defects or mirror movements. This is why a multi-system evaluation is recommended at diagnosis, including kidney imaging and hearing tests. NCBI+2PMC+2

13. Does treatment differ between males and females?
    The overall goals are similar—induce puberty, protect bones and support fertility—but the hormone types and dosing differ. Males usually receive testosterone or gonadotropins; females receive estrogen–progestin and may use gonadotropins or GnRH for fertility. Synapse+3OUP Academic+3Cleveland Clinic+3

14. Is Kallmann syndrome common?
    No, it is rare. Estimates suggest about 1 in 30,000 males and 1 in 125,000 females, though exact numbers vary. Many cases may be missed or diagnosed late, especially in settings with limited endocrine services. Wikipedia+1

15. What is the most important step I can take now?
    The most important step is to work closely with an experienced endocrinologist, follow your treatment plan, and attend regular reviews. Combine this with healthy lifestyle choices, mental-health support and honest communication with family or partners. With this comprehensive approach, most people with Kallmann syndrome can live full, active lives. OUP Academic+2PMC+2

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: December o2 , 2025.

Rabson–Mendenhall syndrome (RMS) is a very rare genetic disease in which the body’s cells do not respond properly to insulin. This problem is called severe insulin resistance. Insulin is a hormone made by the pancreas that helps sugar (glucose) move from the blood into the cells to be used as energy. In RMS, the insulin “key” is present in very high amounts, but the “locks” (insulin receptors) on the cells are not working well. As a result, the body makes huge amounts of insulin, but blood sugar control is still poor. Over time this leads to serious problems with growth, metabolism, and many organs. National Organization for Rare Disorders+1

Rabson–Mendenhall syndrome is an extremely rare genetic disease where the body’s cells cannot respond properly to insulin because of changes (mutations) in the insulin-receptor gene (INSR). This causes severe insulin resistance, which means the pancreas makes huge amounts of insulin, but blood sugar still stays high and swings between low and very high levels. Children are usually very small, have thin muscles, very little body fat, dark thick skin patches called acanthosis nigricans, unusual face, teeth, hair and nail changes, and enlarged organs. Over time they almost always develop difficult-to-control diabetes and its complications. There is no cure, so treatment focuses on tight glucose control, preventing infections and complications, and supporting growth and quality of life. NCBI+2National Organization for Rare Disorders+2

RMS is caused by changes (mutations) in the insulin receptor gene (INSR) on chromosome 19. This gene gives the instructions for making insulin receptors. When this gene is faulty, the receptors have an abnormal shape or are too few in number. Insulin cannot bind or signal correctly, so the body needs more and more insulin to try to keep blood sugar normal. This is why patients with RMS have very high insulin levels in the blood (hyperinsulinemia). PMC+1

Rabson–Mendenhall syndrome is inherited in an autosomal recessive way. This means a child is affected when they receive one faulty INSR gene from each parent. The parents usually carry one faulty gene but are healthy themselves. If both parents are carriers, there is a 25% chance in each pregnancy that the child will have RMS. MedlinePlus+1

RMS usually starts in early childhood. Children are often very small, very thin with little body fat, and have special facial, dental, skin, and nail changes. They often develop very dark, thick skin in the skin folds (acanthosis nigricans), early or abnormal puberty, and later severe diabetes that is hard to control. The condition is part of a spectrum of severe insulin resistance syndromes, sitting between Donohue syndrome (more severe) and type A insulin resistance syndrome (milder). jcrpe.org+1

Other names of Rabson–Mendenhall syndrome

Doctors and textbooks may use different names or phrases when they talk about Rabson–Mendenhall syndrome. Some of these are:

1. Rabson–Mendenhall syndrome (RMS)
   This is the standard and most common name. It comes from the first doctors who described it. Wikipedia+1

2. Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities
   This long name describes three key features often seen in RMS: enlargement of the pineal gland in the brain, very strong resistance to insulin causing diabetes, and many body (somatic) abnormalities such as facial, nail, and growth changes. Wikipedia+1

3. Syndrome of severe insulin resistance due to INSR mutations (Rabson–Mendenhall phenotype)
   In scientific papers, RMS is often called a syndrome of severe or extreme insulin resistance caused by changes in the insulin receptor gene (INSR). This highlights that the root problem is in the receptor. OUP Academic+1

4. Intermediate insulin receptoropathy on the severe insulin resistance spectrum
   Some authors describe RMS as an “intermediate” clinical form between the very severe Donohue syndrome (leprechaunism) and the milder type A insulin resistance. All of these are sometimes grouped as insulin receptoropathies. jcrpe.org+1

Types of Rabson–Mendenhall syndrome

There is no single official “type” classification used in all books, but doctors often talk about different clinical forms of RMS based on age of onset, severity, and genetic changes. These “types” are practical groups to help understand how different children can look and behave. OUP Academic+1

1. Classic childhood Rabson–Mendenhall syndrome
   This is the typical form described in many case reports. Children show obvious features in early childhood: short stature, lack of fat, dental and nail abnormalities, dark thick skin changes, and later very severe diabetes that is hard to control. They often survive longer than children with Donohue syndrome but still have serious health problems. MedlinePlus+1

2. Early-infantile severe Rabson–Mendenhall syndrome
   Some babies show signs very early, sometimes even soon after birth. They may have extreme failure to thrive, very high insulin levels, and early diabetic ketoacidosis. Their course is more severe and closer to Donohue syndrome, but their features fit more with RMS. Bangladesh Journals Online+1

3. Atypical or mild Rabson–Mendenhall-like insulin receptor syndrome
   A few patients with INSR mutations have features similar to RMS but milder or appearing later. They may have severe insulin resistance, acanthosis nigricans, and growth problems, but less obvious facial or dental changes. Some authors call these “atypical RMS” or “INSR-related insulin resistance.” jcrpe.org+1

4. Rabson–Mendenhall syndrome with additional organ problems
   Some reported cases describe RMS with extra problems such as heart defects, kidney changes, or very large pineal glands. These are not separate genetic types, but they show that the same basic disease can affect different organs in different people. jcrpe.org+1

Causes of Rabson–Mendenhall syndrome

In reality, the main cause of RMS is biallelic (both copies) mutation of the insulin receptor (INSR) gene. The list below breaks this single core cause into related genetic and risk factors to help understanding.

1. Mutations in the INSR gene
   Changes (mutations) in the insulin receptor gene damage the structure or number of insulin receptors on cells. This is the central cause of RMS. PMC+1

2. Autosomal recessive inheritance
   The disease appears when a child inherits one faulty INSR gene from each carrier parent. Carriers have one normal copy and one changed copy but usually have no symptoms. MedlinePlus

3. Missense mutations in the alpha subunit of the receptor
   Many patients have “missense” mutations that change a single amino acid in the alpha part of the receptor. This can reduce insulin binding and signaling and is often linked to more severe disease. PMC+1

4. Mutations that reduce the number of insulin receptors on cell surfaces
   Some genetic changes lower the amount of receptor that reaches the cell surface. Fewer receptors mean less insulin can act, even when levels are very high. ScienceDirect

5. Mutations affecting receptor signaling after insulin binding
   In other cases, insulin can still bind, but signaling inside the cell is disturbed. This “post-receptor” problem also causes severe insulin resistance. Wikipedia+1

6. Compound heterozygous INSR mutations
   Some patients have two different mutations, one on each copy of the gene. Together these “compound” changes can severely damage receptor function and cause RMS. Frontiers+1

7. Nonsense or frameshift mutations
   More drastic changes like nonsense or frameshift mutations can stop the receptor from being made correctly, leading to very strong insulin resistance and early, severe disease. ScienceDirect+1

8. Splice-site mutations in INSR
   Some mutations affect how the gene’s RNA is spliced. This can remove or change important parts of the receptor, again leading to poor insulin action. ScienceDirect+1

9. Consanguineous (related) parents
   When parents are blood relatives (for example, cousins), they are more likely to carry the same rare faulty gene. This increases the chance that a child will inherit two faulty INSR copies and develop RMS. Wikipedia+1

10. Family history of severe insulin resistance syndromes
    A history of Donohue syndrome, RMS, or type A insulin resistance in close family members suggests that carrier INSR mutations may be present and can lead to RMS in offspring. OUP Academic+1

11. New (de novo) INSR mutations in a child
    Sometimes a mutation happens for the first time in the egg or sperm. The parents are not carriers, but the child has a new INSR mutation that can cause severe insulin resistance and RMS-like features. Frontiers+1

12. Mutations that reduce receptor recycling
    Some changes may cause receptors to be removed from the cell surface too quickly or not recycled properly, making cells less responsive to insulin over time. ScienceDirect

13. Mutations that affect receptor glycosylation or folding
    If the receptor is not folded or processed properly inside the cell, it may not reach the cell surface or may not work normally, causing severe insulin resistance. PMC+1

14. Mutations that specifically impair growth signaling pathways
    Insulin receptors are linked to growth pathways (for example, insulin-like growth factor signaling). Some mutations may strongly disturb these pathways, leading to growth failure and skeletal changes typical of RMS. ScienceDirect+1

15. Mutations that mostly impair metabolic (glucose) pathways
    Other mutations may mainly affect glucose handling, leading to big swings between low and high blood sugar and early diabetes in RMS patients. Wikipedia+1

16. Mutations shared with the Donohue–RMS–type A spectrum
    Certain INSR mutations appear in different family members with different severity. In some, the same gene change can cause Donohue syndrome or RMS, showing that the same underlying cause can give different clinical pictures. jcrpe.org+1

17. Additional genetic modifiers outside INSR
    Other genes that affect insulin signaling, growth, or metabolism may modify how severe the INSR mutation appears. These modifiers do not cause RMS alone, but they can worsen or soften the clinical picture. OUP Academic+1

18. Environmental triggers that reveal the genetic defect
    The underlying cause is still genetic, but stressors like infections, fast growth phases, or poor nutrition can unmask or worsen insulin resistance, making RMS features appear earlier or more clearly. Bangladesh Journals Online+1

19. Poor access to early diagnosis and care
    This does not cause the gene defect, but lack of early diagnosis may allow metabolic problems to become severe, making the clinical picture of RMS much worse. PubMed+1

20. Delayed recognition of severe insulin resistance in childhood
    If early signs like dark skin thickening or growth failure are missed, diabetes and organ damage may progress unchecked. Again, the genetic cause is the same, but late recognition increases complications and severity. Cureus+1

Symptoms of Rabson–Mendenhall syndrome

1. Poor growth and short stature
   Children with RMS are usually small even before birth and remain short for their age. They often have failure to thrive, which means they do not gain weight and height as expected, even with proper feeding. MedlinePlus+1

2. Very little body fat and muscle wasting
   Many affected children look extremely thin, with very little fat under the skin and reduced muscle mass. This happens because insulin cannot properly help store energy and build tissues. Bangladesh Journals Online+1

3. Special facial appearance (coarse, aged facies)
   The face can look older than the child’s age, with a prominent jaw (prognathism), big lips, and coarse facial features. This “aged” look is a classic feature described in the first reported cases. Wikipedia+1

4. Dental abnormalities
   Children may have early tooth eruption, abnormal tooth shape, or poor dental enamel. Teeth can be crowded or spaced in an unusual way. These problems reflect abnormal growth of the facial bones and tooth structures. Wikipedia+1

5. Nail thickening and abnormalities
   The fingernails and toenails are often very thick and may grow in an irregular way. This nail hypertrophy is part of the somatic abnormalities seen in RMS. Physiology Journals+1

6. Dark, thick skin in body folds (acanthosis nigricans)
   Acanthosis nigricans is a key sign of severe insulin resistance. The skin of the neck, armpits, groin, and other folds becomes dark, velvety, and thick. It is caused by high insulin levels stimulating skin cells. Frontiers+1

7. Excess body hair (hypertrichosis or hirsutism)
   Many patients have very thick hair on the head and increased body hair. High insulin levels and hormonal changes can stimulate hair growth in unusual patterns. Physiology Journals+1

8. Enlarged genitalia and early puberty features
   Boys may have enlarged penis and testes, and girls may have enlarged clitoris and early breast development or polycystic ovaries. These changes are due to hormonal imbalance caused by severe insulin resistance. Wikipedia+1

9. Wide range of blood sugar swings
   Because insulin does not work properly, blood sugar can be very low during fasting (hypoglycemia) and very high after meals (hyperglycemia). Over time, persistent high sugar levels lead to diabetes mellitus. MedlinePlus+1

10. Diabetic ketoacidosis and serious metabolic crises
    Many children with RMS develop diabetic ketoacidosis (DKA), which is a life-threatening state with high blood sugar, acid buildup, dehydration, and breathing problems. DKA is a common cause of hospital admissions and can cause death if not treated quickly. jkms.org+1

11. Recurrent infections
    Poor diabetes control and metabolic stress weaken the immune system. Children with RMS often have repeated infections, such as skin, lung, or urinary infections, which further harm overall health. Wikipedia+1

12. Abdominal swelling and organ enlargement
    Some patients have enlarged liver, ovaries, or other organs, which can cause a swollen abdomen. Organ enlargement may be due to fat buildup, hormonal effects, or tissue overgrowth. Bangladesh Journals Online+1

13. Pineal gland hyperplasia and possible neurological effects
    Enlargement of the pineal gland is reported in classic RMS. It may be seen on imaging and sometimes affects hormone regulation related to sleep and puberty, although symptoms can vary. Wikipedia+1

14. Fatigue, weakness, and exercise intolerance
    Poor energy use and repeated episodes of high and low blood sugar cause tiredness and poor stamina. Children may not be able to play or exercise like their peers. Bangladesh Journals Online+1

15. Shortened life expectancy
    Unfortunately, because of severe insulin resistance, hard-to-control diabetes, and repeated metabolic crises, many patients with RMS have a reduced life span, often dying in childhood or early adolescence despite treatment. Wikipedia+1

Diagnostic tests for Rabson–Mendenhall syndrome

Doctors use a mix of physical examination, manual/bedside tests, laboratory and pathological tests, electrodiagnostic tests, and imaging to diagnose RMS and to rule out other conditions.

Physical examination

1. Complete general physical exam with growth chart review
   The doctor carefully checks the child’s height, weight, and head size and plots them on growth charts. RMS often shows very low height and weight for age and sometimes a relatively large head. The doctor also notes body proportion, muscle bulk, and fat stores. This helps confirm failure to thrive and growth problems. MedlinePlus+1

2. Skin examination for acanthosis nigricans and hair changes
   The skin of the neck, armpits, groin, and other folds is examined for dark, thick, velvety patches typical of acanthosis nigricans. The doctor also looks for unusual hair growth (hypertrichosis or hirsutism). These findings strongly suggest severe insulin resistance such as RMS. Frontiers+1

3. Head, face, teeth, and nail examination
   The doctor examines the shape of the head and face, looking for coarse or aged features and a prominent jaw. The teeth are checked for early eruption and abnormal shape. Nails are checked for unusual thickness. These visible features, combined with growth and skin signs, point toward RMS rather than more common forms of diabetes. Wikipedia+1

Manual and bedside tests

4. Blood pressure and heart rate measurement
   Blood pressure and pulse are measured at each visit. Long-term severe insulin resistance and diabetes can affect the heart and blood vessels. Very low or very high blood pressure can signal dehydration, shock, or other complications such as diabetic ketoacidosis. accessanesthesiology.mhmedical.com+1

5. Anthropometric measurements (BMI, waist circumference, skinfolds)
   Body mass index and waist circumference give a picture of body fat distribution. In RMS, children are usually underweight with reduced fat mass, but detailed measurements help show the pattern and track it over time. Skinfold thickness can confirm that there is very little subcutaneous fat. Bangladesh Journals Online+1

6. Pubertal staging (Tanner staging)
   The doctor checks breast development in girls, genital size in boys, and body hair in both. This helps see if puberty is early, normal, or delayed. RMS can be linked to early or abnormal puberty and enlarged genitalia. Tanner staging gives an objective way to record these changes. Wikipedia+1

7. Neurological bedside examination
   Simple tests of strength, reflexes, sensation, and coordination are done. Long-term uncontrolled diabetes can damage nerves (neuropathy). Finding early nerve problems encourages stricter control and further tests. accessanesthesiology.mhmedical.com+1

Laboratory and pathological tests

8. Fasting plasma glucose test
   A blood sample is taken after an overnight fast to measure fasting sugar. In early RMS, fasting sugar may be low or high. In later stages, it is often very high due to severe insulin resistance and diabetes. This test gives a baseline for blood sugar control. Wikipedia+1

9. Oral glucose tolerance test (OGTT)
   The child drinks a measured amount of glucose, and blood sugar is measured at several times afterward. In RMS, the blood sugar levels rise much higher than normal and stay high for longer, showing that insulin is not working well. This test is a standard way to show insulin resistance and diabetes. Wikipedia+1

10. Fasting insulin and C-peptide levels
    Blood levels of insulin and C-peptide (a marker of how much insulin the body makes) are measured. In RMS, these levels are extremely high because the pancreas is trying to overcome the severe resistance of the body’s cells. Very high insulin levels with poor glucose control are a key clue to RMS. jkms.org+1

11. Hemoglobin A1c (HbA1c)
    HbA1c shows the average blood sugar level over the previous 2–3 months. In RMS, HbA1c is often very high, showing long-standing poor control. This test helps monitor how well treatment is working over time. accessanesthesiology.mhmedical.com+1

12. Lipid profile (cholesterol and triglycerides)
    Blood fats are measured because severe insulin resistance and diabetes can cause high triglycerides and other lipid problems. Abnormal lipids add to the risk of heart and blood vessel disease, even in young patients. ResearchGate+1

13. Basic metabolic panel and liver–kidney function tests
    These tests measure electrolytes, kidney function, and liver enzymes. They help detect complications of diabetes, dehydration, and drug side effects. Abnormal results may appear in episodes of diabetic ketoacidosis or with long-term organ stress. accessanesthesiology.mhmedical.com+1

14. Hormone tests (IGF-1, growth hormone, thyroid, adrenal, and sex hormones)
    Because insulin signaling interacts with growth and many hormone systems, doctors often test insulin-like growth factor-1, growth hormone, thyroid hormones, cortisol, and sex hormones. Abnormal patterns can explain growth failure, early puberty, or other endocrine features seen in RMS. ScienceDirect+1

15. Autoantibody tests to rule out type 1 diabetes
    Blood tests for islet-cell antibodies, GAD antibodies, and other markers help to exclude type 1 diabetes. In RMS, these antibodies are usually negative, which supports a diagnosis of genetic insulin receptor disease rather than autoimmune diabetes. Cureus+1

16. Genetic testing for INSR mutations
    This is the most specific test. DNA sequencing looks for mutations in the insulin receptor gene. Finding two harmful mutations (one on each copy of the gene) confirms the diagnosis of Rabson–Mendenhall syndrome. Genetic testing also allows carrier testing of family members and helps with genetic counseling. PMC+1

Electrodiagnostic tests

17. Nerve conduction studies and electromyography (EMG)
    If there are symptoms of numbness, tingling, or weakness, nerve conduction tests and EMG can measure how well nerves and muscles work. Chronic, severe diabetes in RMS can cause peripheral neuropathy. These tests help document nerve damage and guide management. accessanesthesiology.mhmedical.com+1

18. Electrocardiogram (ECG)
    An ECG records the electrical activity of the heart. It is used to check for heart rhythm problems or strain on the heart, which can be caused by electrolyte imbalances, acidosis, or long-term metabolic stress in children with RMS. accessanesthesiology.mhmedical.com+1

Imaging tests

19. Abdominal and pelvic ultrasound
    Ultrasound uses sound waves to produce images of the liver, pancreas, kidneys, ovaries, and other organs without radiation. In RMS, ultrasound can show fatty liver, enlarged ovaries with cysts, or other organ changes. It also helps rule out other causes of abdominal swelling. Bangladesh Journals Online+1

20. Brain MRI or CT focusing on the pineal gland and pituitary
    Brain imaging can detect pineal hyperplasia, which is enlargement of the pineal gland and is a classic feature in many RMS cases. MRI gives detailed images of brain structures and hormone-related glands. Finding pineal hyperplasia together with severe insulin resistance and typical body features strongly supports a diagnosis of RMS. Wikipedia+1

Overall treatment goals in Rabson–Mendenhall syndrome

In Rabson–Mendenhall syndrome, the main goals are to keep blood sugar as stable and safe as possible, avoid diabetic ketoacidosis and severe hypoglycemia, support growth and puberty, prevent eye, kidney, nerve and heart complications, and manage skin, dental and hormonal problems. Because the disease is so rare, doctors often use treatments that are proven for severe insulin resistance or type 2 diabetes and then carefully adapt them to each child, usually combining very high-dose insulin, insulin-sensitizing drugs, newer diabetes medicines, intensive nutrition and strong infection prevention. Care is best in a multidisciplinary team that includes endocrinology, nutrition, dentistry, ophthalmology, cardiology, nephrology, psychology and clinical genetics. ResearchGate+3MDPI+3Bangladesh Journals Online+3

Non-pharmacological treatments

1. Structured medical nutrition therapy
   A specialist dietitian designs a meal plan with controlled carbohydrate, adequate protein and healthy fats to reduce big sugar spikes after meals. Food is spread across the day in small, regular meals and snacks. This helps avoid both high and low blood sugar swings. The plan is constantly adjusted based on growth, insulin dose and lab results. Parents and caregivers are trained to weigh foods, read labels and match carbohydrate intake with insulin where possible. NCBI+1

2. Low-glycemic-index carbohydrate pattern
   Using low-glycemic foods (whole grains, pulses, non-starchy vegetables, some fruits) makes glucose enter the blood more slowly, so insulin and other drugs have a better chance to work. This can soften sharp peaks of blood sugar that are common in severe insulin resistance. Families learn which traditional foods are low GI and how to cook them in simple ways, avoiding deep-fried and highly refined items like white bread and sugary drinks. MDPI

3. Frequent small meals and bedtime snacks
   Because blood sugar in Rabson–Mendenhall syndrome can crash to low levels between meals and surge after eating, many children do better with 5–6 small meals or snacks per day instead of three big meals. A slow-digesting bedtime snack with some protein and fat can prevent night-time hypoglycemia. The exact timing is matched to insulin or other drug action curves and glucose-monitoring results. Europe PMC+1

4. Intensive diabetes education for family
   Parents and older children learn how to check blood glucose, recognize early symptoms of low or high sugar, count carbohydrates, and adjust food during illness. Education is repeated many times, because treatment is complex and stressful. Clear, simple written plans for “sick days” and for emergencies (such as vomiting, fever or breathing problems) are essential to reduce hospital admissions and diabetic ketoacidosis. MDPI+1

5. Continuous glucose monitoring (CGM)
   CGM devices measure glucose in tissue fluid every few minutes and show patterns and alarms for highs and lows. In children with Rabson–Mendenhall syndrome, CGM helps doctors understand rapid glucose changes and adapt insulin and other therapies more safely. It can reduce the burden of finger-pricks and give parents more confidence at night, though results still need careful interpretation by specialists. MDPI+1

6. Individualized physical activity program
   Gentle, regular physical activity such as walking, age-appropriate play, swimming or cycling improves insulin sensitivity in muscles and helps control body weight. In Rabson–Mendenhall syndrome, exercise plans must consider small body size, heart status and fatigue. Activity should be combined with glucose checks before and after to avoid hypoglycemia, and caregivers learn how to adjust food or insulin around exercise. MDPI

7. Skin care for acanthosis nigricans and infections
   Thick, dark, folded skin areas can cause itching, odor and recurrent fungal or bacterial infections. Daily gentle washing, drying folds carefully, using non-perfumed emollients, and prompt treatment of fungal rash help comfort and hygiene. Better glucose control may slowly reduce acanthosis over time, but cosmetic change is often limited, so psychological support and healthy body-image counseling are important. Pediatric Endocrinology Journal+1

8. Dental and oral-health management
   Abnormal teeth, early eruption and gum overgrowth are common. Regular dental visits, fluoridated toothpaste, professional cleaning and early treatment of cavities reduce pain and infection risk. In some children, orthodontic or surgical correction of severe dental problems improves chewing, nutrition and self-esteem. Dentists and endocrinologists coordinate to time procedures when glucose is reasonably controlled. Wikipedia+1

9. Eye screening and visual rehabilitation
   Because long-term high blood sugar increases risk of diabetic retinopathy and other eye problems, children need regular eye exams from an ophthalmologist familiar with pediatric diabetes. Early detection of retinal changes allows laser therapy or injections when appropriate. If visual problems develop, low-vision aids, special school support and safety adaptations at home can maintain independence. NCBI+1

10. Kidney and blood-pressure monitoring with lifestyle support
    Rabson–Mendenhall syndrome can lead to diabetic kidney disease. Regular blood-pressure checks, urine albumin tests and kidney function tests allow early detection. Salt moderation, healthy weight, physical activity and avoidance of nephrotoxic medicines (when possible) are simple but important kidney-protective measures that families can follow with guidance. MDPI+1

11. Vaccination and infection-prevention routines
    Children with brittle diabetes are at extra risk when they have infections, because fever and dehydration can trigger diabetic ketoacidosis. Keeping all routine vaccines up to date, including influenza and pneumococcal vaccines when recommended, careful handwashing, and early treatment of skin, ear and respiratory infections can reduce serious illness episodes. NCBI+1

12. Psychological and social-support therapy
    Living with a visible rare disease, frequent hospital visits and strict treatment is emotionally heavy for both child and family. Access to counselors, psychologists or social workers helps with anxiety, low mood, school difficulties and family stress. Support groups (even online, because the condition is so rare) can reduce isolation and allow sharing of practical tips. MDPI+1

13. Growth and puberty monitoring with endocrine support
    Regular measurement of height, weight, puberty stage and hormone levels allows early recognition of growth failure or abnormal puberty. Non-drug approaches include optimizing nutrition, managing chronic illness and planning school and physical activities in ways that respect the child’s energy and size, while medical hormone therapy (if used) is prescribed only by specialists. NCBI+1

14. Foot-care training
    As children get older and diabetes duration increases, nerves and blood vessels in the feet may be affected. Teaching families to inspect feet daily, choose soft protective footwear, treat small cuts quickly and avoid walking barefoot helps lower the risk of ulcers and infections later in life. This habit is simple but very important in any severe diabetes condition. MDPI

15. Sleep-hygiene and daily-routine structuring
    Stable sleep and wake times and regular daily routines can help with timing of meals, insulin doses and other medicines. Poor sleep may worsen insulin resistance and make children and parents more prone to mistakes in dosing. Simple steps like avoiding screens before bed, keeping a calm bedtime routine and planning nighttime glucose checks thoughtfully can help. MDPI+1

16. Stress-management techniques for family and child
    Chronic stress raises hormones that can worsen insulin resistance and glucose control. Relaxation breathing, simple mindfulness exercises, age-appropriate play therapy, and family problem-solving sessions can all help. Even short, regular calm periods during the day can lower stress for caregivers and child. MDPI+1

17. Genetic counseling for family planning
    Because Rabson–Mendenhall syndrome is autosomal recessive, there is a one-in-four chance that another child of the same parents could be affected if both parents carry the mutation. Genetic counseling explains this risk in simple language, offers carrier testing to relatives when appropriate, and discusses prenatal or preimplantation options for future pregnancies, always respecting family values and laws. Pediatric Endocrinology Journal+1

18. School-based care plans and accommodations
    Teachers and school staff need a clear written plan about when to check glucose, what symptoms to watch for, and what to do for hypoglycemia or hyperglycemia. Extra time for snacks, water and toilet breaks, and flexibility around physical-education classes can make school safer and more welcoming. This also reduces parental anxiety during school hours. MDPI+1

19. Home-safety planning for severe lows or highs
    Families are taught how to keep fast-acting carbohydrate (like glucose gel or juice) and emergency contact numbers always available, and how to respond if the child becomes confused or unresponsive. Some families may be trained in emergency glucagon use if recommended. Simple written “red flag” instructions on the fridge or phone increase safety. MDPI+1

20. Palliative-care and quality-of-life support when disease is advanced
    Sadly, life expectancy in Rabson–Mendenhall syndrome is often limited, although some individuals live into adulthood. When complications become severe, palliative-care teams can help focus on comfort, pain control, emotional support and family goals, alongside or instead of aggressive hospital treatments, always guided by the family and local ethical standards. NCBI+2MDPI+2

Drug treatments

Key note: No medicine is currently approved specifically for Rabson–Mendenhall syndrome. Most drugs below are licensed for diabetes or lipodystrophy and have been used off-label in small case reports of Rabson–Mendenhall syndrome or related severe insulin-resistance syndromes. All use must be under expert supervision.

1. Regular human insulin (e.g., HUMULIN R, NOVOLIN R)
   Class: Short-acting human insulin. Usual use: Given before meals and sometimes as continuous IV infusion during crises to lower high glucose and ketones. Mechanism: Replaces natural insulin, helping glucose move into muscle and fat and suppressing liver glucose production. Dosing: Completely individualized and often extremely high in Rabson–Mendenhall syndrome; labels stress careful titration to blood glucose and frequent monitoring. Side effects: Hypoglycemia, weight gain, local injection reactions and rare serious allergy. Bangladesh Journals Online+3pi.lilly.com+3FDA Access Data+3

2. Intermediate-acting NPH insulin (HUMULIN N)
   Class: Intermediate-acting human insulin. Purpose: Provides basal insulin coverage between meals and overnight. Mechanism: Slowly absorbed insulin suspension that maintains background insulin levels. Dosing/time: Typically once or twice daily, timing adjusted to meals and risk of nocturnal hypoglycemia; dosing must be personalized. Side effects: Hypoglycemia, especially overnight, weight gain and injection-site issues. FDA Access Data+1

3. Long-acting insulin analog (insulin glargine – LANTUS and similar)
   Class: Long-acting basal insulin analog. Purpose: Provides a relatively flat 24-hour insulin level to help control fasting and between-meal glucose. Mechanism: Modified insulin structure causes slow release from the injection site. Dosing: Usually once daily; labels stress starting with low doses and then titrating according to fasting glucose and total insulin needs. Side effects: Hypoglycemia, injection-site reactions, and weight gain; requires careful monitoring in children. FDA Access Data+1

4. Rapid-acting insulin analog (e.g., lispro/“MERILOG”-type preparations)
   Class: Rapid-acting insulin analog. Purpose: Covers glucose spikes with meals or correction doses. Mechanism: Slight molecular changes allow very fast absorption and onset. Dosing/time: Injected just before or with meals, with dose adjusted to carbohydrate amount and glucose. Side effects: Hypoglycemia soon after meals if carbohydrate intake is low, local reactions, weight gain. FDA Access Data+1

5. Metformin (GLUCOPHAGE and extended-release forms such as GLUMETZA)
   Class: Biguanide insulin-sensitizing agent. Purpose: Helps lower hepatic glucose production and improves insulin sensitivity, so extremely high insulin doses may work slightly better. Mechanism: Reduces liver gluconeogenesis and improves peripheral uptake of glucose. Dosing: Started at low dose with food and slowly increased; extended-release tablets allow once-daily dosing in older children and adults. Side effects: Gastrointestinal upset, B12 deficiency with long-term use and rare lactic acidosis in high-risk patients. Bangladesh Journals Online+3FDA Access Data+3FDA Access Data+3

6. Pioglitazone (ACTOS)
   Class: Thiazolidinedione (PPAR-γ agonist). Purpose: Improves insulin sensitivity in fat and muscle and may lower insulin requirements in some severe insulin-resistance syndromes. Mechanism: Acts on nuclear receptors to change gene expression related to fat storage and insulin sensitivity. Dosing: Once-daily oral tablets; labels require gradual titration and caution with liver disease or heart failure. Side effects: Fluid retention, weight gain, risk of edema or heart failure, bone-fracture risk and rare liver toxicity. FDA Access Data+2FDA Access Data+2

7. Empagliflozin (JARDIANCE – SGLT2 inhibitor)
   Class: Sodium–glucose co-transporter-2 (SGLT2) inhibitor. Purpose: Helps the kidneys pass extra glucose into the urine, lowering blood sugar independently of insulin and sometimes improving control in Rabson–Mendenhall case reports. Mechanism: Blocks glucose re-absorption in kidney tubules. Dosing: Once-daily oral tablet; labels advise dose adjustments with kidney function and monitoring for dehydration. Side effects: Genital and urinary infections, dehydration, hypotension and ketoacidosis risk, especially when insulin dose is reduced. FDA Access Data+2FDA Access Data+2

8. Combination empagliflozin + metformin (SYNJARDY)
   Class: SGLT2 inhibitor plus biguanide. Purpose: Provides dual mechanisms (renal glucose loss + hepatic inhibition) in one pill for patients whose caregivers and doctors can handle complex monitoring. Mechanism: Combines actions of empagliflozin and metformin. Dosing: Twice-daily tablets with meals; titrated carefully. Side effects: Mix of both components’ risks, including GI upset, genital infections and rare lactic acidosis or ketoacidosis. FDA Access Data+1

9. Combination empagliflozin + linagliptin (GLYXAMBI)
   Class: SGLT2 inhibitor plus DPP-4 inhibitor. Purpose: Adds renal glucose loss to incretin-based improvement in insulin secretion and glucagon suppression. Mechanism: Linagliptin blocks DPP-4, raising GLP-1 and GIP levels; empagliflozin increases urinary glucose excretion. Dosing: Once-daily tablets; adjustments for kidney function may be necessary. Side effects: Genital infections, possible pancreatitis, rare allergic reactions and ketoacidosis risk; all need monitoring in fragile patients. FDA Access Data+1

10. Linagliptin (TRADJENTA)
    Class: DPP-4 inhibitor. Purpose: Improves post-meal blood sugar by raising endogenous GLP-1 and GIP levels, which enhance insulin secretion and reduce glucagon in a glucose-dependent manner. Mechanism: Inhibits DPP-4 enzyme that normally breaks down incretin hormones. Dosing: Once-daily 5-mg oral tablet in adults; labels emphasize caution with hypoglycemia when combined with insulin or sulfonylureas. Side effects: Nasopharyngitis, cough, joint pain and rare serious hypersensitivity reactions such as angioedema. FDA Access Data+2FDA Access Data+2

11. Liraglutide (VICTOZA / SAXENDA – GLP-1 receptor agonist)
    Class: GLP-1 receptor agonist. Purpose: Slows gastric emptying, enhances glucose-dependent insulin release and reduces appetite, which together can improve glucose control and weight profile. Mechanism: Mimics incretin hormone GLP-1 at its receptor. Dosing: Once-daily subcutaneous injection with gradual dose escalation. Side effects: Nausea, vomiting, diarrhea, risk of pancreatitis and a boxed warning about thyroid C-cell tumors in animals; contraindicated in certain thyroid conditions. FDA Access Data+3FDA Access Data+3FDA Access Data+3

12. Sulfonylureas (e.g., glimepiride – as in DUETACT)
    Class: Insulin secretagogues. Purpose: Stimulate pancreatic insulin release, sometimes used when residual beta-cell function is present. Mechanism: Close ATP-sensitive potassium channels in beta cells, triggering insulin secretion. Dosing: Once or twice daily oral tablets; labels stress starting with low doses to avoid hypoglycemia. Side effects: Hypoglycemia, weight gain, and rarely severe allergy or liver issues. FDA Access Data+1

13. Hydroxychloroquine (off-label metabolic use)
    Class: Antimalarial and disease-modifying anti-rheumatic drug (DMARD). Purpose: In adults with type 2 diabetes, studies show better insulin sensitivity and lower HbA1c when used as an add-on, so some teams have considered it in extreme insulin resistance. Mechanism: Complex immunomodulatory and cellular effects that seem to reduce inflammation and improve insulin signaling. Side effects: Eye toxicity with long use, GI upset, skin reactions and potential heart-rhythm problems; needs careful monitoring. PMC+2SpringerLink+2

14. Recombinant IGF-1 (mecasermin – INCRELEX)
    Class: Recombinant human insulin-like growth factor-1. Purpose: Approved for severe primary IGF-1 deficiency but has been explored in severe insulin-receptor defects to bypass the defective receptor and improve growth and metabolic control. Mechanism: Stimulates IGF-1 receptors, promoting growth and insulin-like metabolic actions. Dosing: Subcutaneous injections based on body weight, usually twice daily with meals or snacks to reduce hypoglycemia risk. Side effects: Hypoglycemia, enlarged tonsils, jaw pain, intracranial hypertension and local reactions. FDA Access Data+2FDA Access Data+2

15. rhIGF-1 / IGFBP-3 complex (mecasermin rinfabate – IPLEX, historical)
    Class: IGF-1 plus binding protein complex. Purpose: Previously used experimentally in severe insulin-receptor defects to provide steady IGF-1 exposure; now largely withdrawn but mentioned in older reports. Mechanism: IGF-1 bound to IGFBP-3 prolongs half-life and modulates tissue delivery. Side effects: Similar to IGF-1 alone, including hypoglycemia and tissue overgrowth; now mainly of historical and research interest. FDA Access Data+1

16. Metreleptin (MYALEPT – leptin analog)
    Class: Recombinant leptin analog. Purpose: Approved for generalized lipodystrophy; in that setting it improves insulin resistance and hypertriglyceridemia, so some case reports and reviews discuss its potential role in extreme insulin resistance syndromes. Mechanism: Replaces deficient leptin, normalizing appetite and endocrine signals, improving metabolic control. Dosing: Daily subcutaneous weight-based dosing under strict REMS program. Side effects: Risk of neutralizing antibodies, lymphoma signal, hypoglycemia (when combined with insulin), and injection-site reactions. MDPI+3FDA Access Data+3FDA Access Data+3

17. Statins (e.g., atorvastatin – LIPITOR)
    Class: HMG-CoA reductase inhibitors. Purpose: In older patients with long-standing severe insulin resistance and high lipids, statins lower LDL cholesterol and reduce cardiovascular risk. Mechanism: Block a key step in cholesterol synthesis, up-regulating LDL receptors in the liver. Dosing: Once-daily oral tablets with dose adjusted to lipid targets and tolerability. Side effects: Muscle pains, rare severe muscle injury, liver enzyme elevation; recent recalls of some generics highlight the need for quality and monitoring. FDA Access Data+2FDA Access Data+2

18. ACE inhibitors or ARBs (kidney-protective drugs)
    Class: Renin–angiotensin system blockers. Purpose: Protect kidneys and the heart when microalbuminuria or hypertension appears, as in other forms of diabetic nephropathy. Mechanism: Relax blood vessels, reduce intraglomerular pressure and protein leakage. Dosing: Once-daily oral tablets, titrated slowly. Side effects: Cough (ACE inhibitors), high potassium, kidney function changes and rare angioedema. MDPI

19. Low-dose aspirin (selected older patients)
    Class: Antiplatelet agent. Purpose: Sometimes considered for cardiovascular risk reduction in adult patients with diabetes and high risk, though evidence must be weighed against bleeding risk. Mechanism: Irreversibly inhibits platelet COX-1, reducing thromboxane A2 and platelet aggregation. Side effects: Stomach irritation, bleeding, allergy in aspirin-sensitive individuals. MDPI

20. Broad-spectrum antibiotics (for infection management)
    Class: Antibacterial agents (many types). Purpose: In children with Rabson–Mendenhall syndrome, infections can rapidly destabilize glucose and trigger ketoacidosis, so early and appropriate antibiotic treatment for serious infections is critical. Mechanism: Kill or inhibit bacteria depending on class. Side effects: Vary by drug, including allergy, GI upset and microbiome disturbance; careful selection and stewardship are essential. NCBI+2Bangladesh Journals Online+2

(Because of space, dosing details are summarized; in real life they are strictly individualized by specialists.)

Dietary molecular supplements

None of these supplements are proven cures for Rabson–Mendenhall syndrome. They are sometimes discussed to support general metabolic health. Always review them with the treating team because some can interact with medicines.

1. Vitamin D – supports bone health and may modestly improve insulin sensitivity, especially if there is deficiency.

2. Omega-3 fatty acids (fish oil) – can help lower triglycerides and inflammation, which may support cardiovascular health in severe diabetes.

3. Magnesium – low magnesium is linked with poorer glucose control; careful replacement may help if blood levels are low.

4. Chromium – participates in insulin signaling; some studies show small improvements in insulin sensitivity, but evidence is mixed.

5. Alpha-lipoic acid – antioxidant that may help in diabetic nerve pain and oxidative stress.

6. Coenzyme Q10 – mitochondrial cofactor sometimes used to support heart and muscle health in long-term diabetes.

7. Zinc – important for insulin storage and immune function; deficiency correction can support wound healing and infection defense.

8. Myo-inositol – used in some insulin-resistance conditions (e.g., PCOS); it may modestly improve insulin signaling.

9. Probiotics – may improve gut microbiome balance, which is linked to metabolism and inflammation.

10. Soluble fiber (e.g., psyllium, beta-glucan) – slows glucose absorption and improves satiety, helping with post-meal spikes. MDPI+1

(For each supplement, dosing must be individualized; megadoses are not recommended without specialist guidance.)

Immunity-boosting and regenerative / stem-cell-related approaches

1. Optimized nutrition plus standard vaccines
   The safest and most important “immunity booster” is good nutrition, stable blood sugar and full routine vaccination. Poor glucose control itself weakens infection defenses, so the core regenerative step is to improve metabolic control as much as possible with the treatments above. NCBI+1

2. Metreleptin as metabolic and endocrine modulator
   Leptin replacement in severe lipodystrophy improves insulin resistance, lipids and liver fat and may indirectly support immune balance by reducing chronic inflammation. Its potential use in extreme insulin resistance syndromes remains experimental and must be done only in research-level centers under strict REMS safety rules. MDPI+3FDA Access Data+3FDA Access Data+3

3. Recombinant IGF-1 as growth and tissue-support therapy
   IGF-1 has powerful growth and anabolic effects that can support bone, muscle and organ development and partly replace some metabolic insulin actions. In Rabson–Mendenhall syndrome, this may “regenerate” growth velocity, but the risk of hypoglycemia and tissue overgrowth means close monitoring and is still considered a highly specialized treatment. FDA Access Data+1

4. Experimental beta-cell replacement or islet transplantation
   Some researchers discuss pancreatic islet transplantation or future stem-cell-derived beta-cell implants, but because the problem in Rabson–Mendenhall syndrome is mainly at the insulin-receptor level, simply adding more beta cells cannot fully solve resistance. These approaches are experimental and not standard of care for this syndrome. MDPI+1

5. Gene-therapy and gene-editing research for INSR mutations
   In the future, targeted gene therapy or CRISPR-based editing of INSR might offer true regenerative treatment by fixing the underlying defect. Currently this is only at the research and conceptual stage in laboratories; no approved clinical therapy exists yet. Europe PMC+1

6. General immune support: vitamin D, vaccination and infection control
   Rather than “immune-boosting drugs,” specialists focus on correcting vitamin D deficiency, maintaining dental and skin health, avoiding second-hand smoke and treating infections promptly. This practical combination likely improves real-world immune function much more safely than unproven “immune boosters.” NCBI+1

Surgical options

1. Corrective dental and maxillofacial surgery
   Because Rabson–Mendenhall syndrome often causes abnormal teeth, gum overgrowth and jaw changes, some patients need dental extractions, gum reduction or jaw surgery. These operations can improve chewing, nutrition, speech and appearance, helping both medical health and self-confidence. Careful glucose control around the time of surgery reduces infection and healing problems. Wikipedia+1

2. Eye procedures for diabetic retinal disease
   If diabetic retinopathy develops, laser photocoagulation or intra-ocular drug injections may be needed to prevent bleeding or retinal detachment. These are done by ophthalmologists and are timed according to eye-exam findings. The main goal is to preserve vision and prevent blindness. MDPI+1

3. Bariatric (metabolic) surgery in selected older patients
   In rare older adolescents or adults with severe obesity plus insulin resistance, bariatric surgery may be considered to improve weight and metabolic control. However, in Rabson–Mendenhall syndrome many patients are small and not obese, so this option is not common and must be judged very carefully by a multidisciplinary team. MDPI

4. Central venous access or feeding-tube procedures
   Some children need long-term IV access for frequent hospital treatments, or gastrostomy tubes for reliable feeding if oral intake is very difficult. These procedures are supportive, not curative, and are used when benefits clearly outweigh risks of infection and complications. NCBI+1

5. Kidney or pancreas-related surgery in advanced complications
   If severe diabetic kidney failure occurs, kidney transplantation may be considered according to local criteria. Pancreas transplantation is less logical in Rabson–Mendenhall syndrome because the main problem is insulin resistance, not insulin absence, but it may occasionally be discussed in complex individual cases. These major surgeries are rare and reserved for advanced disease. MDPI+1

Prevention strategies

1. Genetic counseling before pregnancy in at-risk families – helps parents understand autosomal-recessive inheritance and possible options, but cannot change existing cases. Pediatric Endocrinology Journal+1

2. Avoiding consanguineous marriage where possible – in families with known INSR mutations, this can reduce the chance of another affected child. Pediatric Endocrinology Journal+1

3. Early diagnosis and referral to expert centers – catching the syndrome early allows earlier glucose control and complication prevention. NCBI+1

4. Tight glucose management from childhood – reduces the risk of eye, kidney and nerve damage later. MDPI+1

5. Routine vaccinations and infection-prevention habits – help avoid crises and hospitalizations. NCBI+1

6. Regular screening for eyes, kidneys, nerves and heart – annual or more frequent checks allow early intervention. MDPI

7. Healthy diet and physical activity for the whole family – support better insulin sensitivity and cardiovascular health. MDPI+1

8. Avoiding unnecessary steroids and other drugs that worsen glucose control – doctors try to choose alternatives when possible. MDPI

9. Smoking avoidance and second-hand smoke reduction – protect heart and blood vessels in children with high metabolic risk. MDPI

10. Mental-health support to maintain treatment adherence – better coping reduces treatment burnout and missed doses. MDPI+1

When to see a doctor urgently

Families should contact a doctor or emergency department immediately if the child has very high blood sugar with vomiting or breathing problems, signs of diabetic ketoacidosis (deep fast breathing, abdominal pain, fruity breath, extreme thirst), repeated low sugars with confusion or seizures, fever and signs of serious infection (such as fast breathing, lethargy, spreading skin redness), chest pain or severe shortness of breath, sudden changes in vision, very little urine output, or unusual drowsiness. Any rapid change from the child’s usual condition in Rabson–Mendenhall syndrome should be taken seriously, because complications can develop quickly. NCBI+2MDPI+2

What to eat and what to avoid

1. Prefer whole grains, lentils, beans and non-starchy vegetables instead of white rice, white bread and refined flour products.

2. Choose lean protein sources (fish, skinless poultry, eggs, tofu, pulses) at each meal to slow glucose rise and support growth.

3. Use healthy fats in small amounts (olive, mustard or other plant oils; nuts and seeds if age-appropriate and safe from choking).

4. Avoid sugary drinks, energy drinks, fruit juices with added sugar and large servings of sweets.

5. Keep portions of high-glycemic foods (white rice, potatoes, sugary snacks) small and combine them with fiber and protein.

6. Limit deep-fried fast foods and processed meats, which worsen insulin resistance and heart risk.

7. Offer water as the main drink; avoid sweetened teas and soft drinks.

8. Spread carbohydrate intake evenly over the day rather than in one huge meal.

9. If advised by the team, use bedtime snacks with complex carbs and some protein to prevent night-time lows.

10. Never start extreme or fad diets without the endocrine and nutrition team, because growth and development are very delicate in this condition. MDPI+2National Organization for Rare Disorders+2

Frequently asked questions

1. Is Rabson–Mendenhall syndrome curable?
   No, it is not currently curable. Because the root problem is a genetic change in the insulin receptor, treatment focuses on managing blood sugar, preventing complications and supporting growth and quality of life. Research into gene-based therapies is ongoing but still experimental. NCBI+2Europe PMC+2

2. How is Rabson–Mendenhall syndrome diagnosed?
   Doctors use physical features, blood-sugar patterns, very high insulin levels, and genetic testing of the INSR gene to confirm the diagnosis. They also rule out other causes of severe insulin resistance. Many families reach diagnosis only after seeing multiple specialists because the condition is so rare. NCBI+2Pediatric Endocrinology Journal+2

3. Why is insulin resistance so extreme in this disease?
   The insulin receptor is like a “lock” on the cell surface. In Rabson–Mendenhall syndrome, changes in the receptor gene make many locks missing or broken. The body tries to compensate by making huge amounts of insulin, but glucose still cannot enter cells properly, so both hyperinsulinemia and unstable glucose levels appear. Pediatric Endocrinology Journal+2Wikipedia+2

4. Why are such high doses of insulin needed?
   Because receptors respond poorly, normal insulin doses have little effect. Case reports describe extremely high doses to achieve only partial control. Even so, blood sugar can swing widely, which is why non-drug measures and additional insulin-sensitizing drugs are often added. MDPI+2Cureus+2

5. Do newer diabetes medicines really help?
   Evidence is limited to small case reports and severe insulin-resistance reviews, but drugs like SGLT2 inhibitors, GLP-1 agonists, DPP-4 inhibitors, thiazolidinediones and metformin can sometimes reduce glucose levels or insulin needs when used carefully with intensive monitoring. Their effect is usually partial, not a complete fix. FDA Access Data+4MDPI+4Bangladesh Journals Online+4

6. Can diet alone control Rabson–Mendenhall syndrome?
   No. Diet is very important but cannot replace insulin and other medical therapies because receptor defects are too severe. A healthy, structured diet works together with medicines to reduce glucose spikes and support growth. NCBI+2National Organization for Rare Disorders+2

7. What is life expectancy?
   Life expectancy varies. Older descriptions reported many children dying in the first or second decade from diabetic ketoacidosis or chronic complications, but more recent case reports with modern therapies show some individuals surviving longer. Because numbers are very small, it is impossible to predict for any one child. Cureus+3NCBI+3NCBI+3

8. Can children with Rabson–Mendenhall syndrome attend regular school?
   Many can, especially with a written care plan, trained staff and flexible allowances for snacks, glucose checks and medical appointments. Some will also need learning support because of illness, fatigue or associated developmental issues. NCBI+1

9. Is pregnancy possible later in life?
   There are very few reports, but some women with related severe insulin-receptor syndromes have had pregnancies with extremely high-risk management. Most people with classic Rabson–Mendenhall syndrome do not live to typical reproductive age, but each case is individual and requires specialized counseling. MDPI+1

10. Are brothers and sisters at risk?
    If both parents carry the same INSR mutation, each pregnancy has a 25% chance of an affected child, 50% chance of a carrier child and 25% chance of a non-carrier. Genetic counseling helps explain this risk and offers testing options. Pediatric Endocrinology Journal+1

11. Can carrier parents stay healthy?
    Yes. Heterozygous carriers usually have normal insulin receptors and are healthy, although some studies suggest they may have slightly higher risk of metabolic issues. They typically do not show the severe features of Rabson–Mendenhall syndrome. Europe PMC+1

12. Is there a special “Rabson–Mendenhall diet”?
    There is no single agreed-upon “syndrome diet.” Most teams use principles from type 1 and type 2 diabetes care: controlled carbohydrates, low-GI foods, healthy fats and proteins, and avoidance of sugary drinks. The exact plan is personalized. MDPI+1

13. Do supplements replace prescribed medicines?
    No. Supplements can sometimes correct deficiencies or support general health, but they cannot substitute for insulin, SGLT2 inhibitors, metformin or other prescribed drugs. Some supplements interact with medicines, so they should only be used with the team’s approval. MDPI+1

14. What research is happening now?
    Research focuses on understanding new INSR mutations, improving combined drug treatments (e.g., adding SGLT2 inhibitors), exploring hormone therapies like recombinant leptin or IGF-1, and in the longer term studying gene- and cell-based approaches. Because the condition is ultra-rare, most information comes from single-patient case reports. Europe PMC+3MDPI+3ResearchGate+3

15. What should families remember day to day?
    The most important daily steps are regular glucose monitoring, following medicine and meal plans, watching for early signs of highs and lows, preventing infections and keeping close contact with the specialist team. Small, consistent actions each day can make a big difference in safety and comfort, even when the disease itself cannot be cured yet. NCBI+2MDPI+2

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: December o2 , 2025.

References

References

References

References

REferences

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.^{[rx, rx, rx]} 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

• a.Multiple sclerosis
• b.NMO
• c.ADEM

• 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

• 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

• a.Anti-Ri (ANNA-2) antibody
• b.CRMP-5-lgG antibody
• c.Anti-amphiphysin IgG antibody
• d.Anti-GAD65 antibody
• e.NMDAR antibody

• 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?

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.

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.

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.

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

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

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.[rx]
• Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance.[rx] 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.[rx][rx] 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

• 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.

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

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.

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

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

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.[rx]
• Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance.[rx] 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.[rx][rx] 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

• 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.

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

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.

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.

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.[rx]
• Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance.[rx] 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.[rx][rx] 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

• 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.

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