Hypotonia

Etiology

Hypotonia is usually present at birth and is frequently diagnosed in early infancy. There are numerous reasons for hypotonia in an infant. It can result from muscle abnormalities, neuromuscular junctions, or central and peripheral nervous systems. It may also present in genetic disorders, metabolic diseases, endocrine problems, and acute or chronic illnesses.[5] In about 50% of the cases of hypotonia, etiology can be determined with a detailed history and physical examination.[2] Central causes include hypoxic encephalopathy, brain anomalies/insults, genetic/chromosomal syndromes, congenital or acquired infections, and disorders of metabolism. Peripheral causes include spinal muscular atrophy, myasthenia gravis, drug/toxin exposure, hereditary neuropathies, muscular dystrophies, congenital or metabolic myopathies, and congenital myotonic dystrophies.[1][5]

Epidemiology

The exact incidence of hypotonia is difficult to determine because it is not a disease but a presenting feature of various diseases.[2][4] The majority of the cases of hypotonia are congenital. Central pathology accounts for most congenital hypotonias. These typically include hypoxic-ischemic encephalopathy or genetic abnormalities. Central hypotonia is seen in up to 60%-80% of cases. Down syndrome is the most common genetic cause of central hypotonia, followed by Prader-Willi syndrome (PWS). Metabolic diseases, including peroxisomal and storage disorders, are rare causes of central hypotonia.[4][5]

Peripheral and unknown causes account for the rest. The most commonly seen peripheral causes include spinal muscle atrophy, congenital muscular dystrophy, and congenital myopathies.[5] Spinal muscular atrophy has an incidence of 1 in 6,000 to 1 in 10,000 live births.[6] Acquired hypotonias can be due to toxins or infections, including infant botulism. Even though worldwide incidence is rare, most cases are diagnosed in the USA, which can be attributed to clinician awareness. In the United States, California, Pennsylvania, and Utah have a high incidence of infant botulism, with about 50% of cases in California.[7]

History and Physical

History

Initial evaluation starts with a detailed history, including family prenatal and perinatal history. The developmental history of the child, as well as of the parents, can also aid in the diagnosis.[3][5] Attention should also be paid to the presence of hypotonia in the family members with a known cause, such as muscular diseases, genetic disorders, and consanguineous marriage.[3] Prenatal and perinatal history includes details about fetal movements, presentation at birth, amniotic fluid amount throughout pregnancy, and complications during delivery. Details regarding maternal exposure to toxins or drugs, any infections during pregnancy, mode of delivery, gestational age, and Apgar score at birth must also be obtained.

Information regarding the onset of hypotonia and the clinical course can also help to determine the etiology. For example, hypotonia at birth with poor Apgar score may indicate hypoxic-ischemic encephalopathy, whereas poor muscle tone developing 12 to 24 hours after birth may indicate a metabolic disorder.[3][4][5] Infants with central hypotonia usually have a higher prevalence of cognitive delays. A standardized neurodevelopmental assessment must be done in older children. The Bayley scale (Bayley-III) may be used. It covers the ages from 1 to 42 months and assesses motor, cognitive, language, and social-emotional domains of development. However, the assessment with Bayley-III or any other standardized scale may be difficult when the infant has a profound weakness.[3] A careful review of all organ systems must be included, as it may aid in diagnosing the underlying etiology.[4]

Physical Examination

A detailed physical examination, along with a comprehensive neurologic examination, must be done. Paying attention to dysmorphic features or any associated congenital malformations. The shape and size of the head must be included as well. Muscular strength should be evaluated in a child with hypotonia. It should also be determined if the hypotonia has progressed or remained static since onset. The infant's tone can be assessed by using 4 maneuvers:

Vertical suspension

In vertical suspension, an infant is held under the arms. A hypotonic infant would slip through the examiner's hands. This mainly assesses the appendicular tone.[3][5]

Horizontal suspension

The horizontal suspension is tested by lifting the infant in a prone position with a hand over the chest and abdomen. Typically, an alert and a term infant would have some flexion of arms and legs and the ability to hold the head above the horizontal for some time. An infant with hypotonia would form an inverted "U" posture.[3][5]

"The Scarf Sign"

"Scarf sign" assesses the appendicular tone in the shoulders. In this, the infant lies supine, and the hand is pulled across the chest as far as possible before encountering resistance. Usually, infant resistance is encountered when the elbow reaches the midline. In a hypotonic infant, the elbow can go beyond the midline before any resistance is encountered.[3]

"Pull-to-sit" maneuver[5][8]

The pull-to-sit maneuver involves pulling a supine infant to a sitting position. Head lag can be noticed in newborns, but it should disappear by 2 months of age. Hypotonic infants would have a significant head lag. This maneuver mainly explains the axial tone in the neck and back muscles. The strength of the shoulder and arms can also be assessed with the "pull to sit" maneuver as the infants flex the arms while attempting it.[3][5]

It is usually challenging to determine muscle strength in an infant. Weakness may be manifest as decreased spontaneous movements. This can be tested by evaluating the cry, suck reflex, spontaneous movements, facial expressions, antigravity movements, and respiratory effort. When assessing weakness in an infant, the course and area of involvement must also be noted.[5] These findings may be confounded in a severe systemic illness (eg, sepsis) or medications (eg, magnesium or sedatives). This can be overcome by examining the patient on 2 separate occasions.[8]

Patients with central hypotonia usually have a depressed level of consciousness, normal muscle strength, reflexes that may be normal or exaggerated, and the persistence of primitive reflexes and clonus. They may also have dysmorphic features and congenital abnormalities, pointing towards a syndromic cause of hypotonia. These findings vary in severity and prevalence, depending on the underlying cause.[2][5]

In the case of peripheral hypotonia, the patient has a variable degree of impairment in moving the extremities against gravity. The infant is usually alert, has a normal sleep-wake pattern, and responds to the surroundings appropriately. There is usually no cognitive impairment; however, gross and fine motor skills might be delayed. The reflexes are usually reduced or absent.[2][4] Patients often have feeding difficulties, respiratory impairment, and impaired ocular and facial movements.[5]

Evaluation

To reach a correct diagnosis in a hypotonic newborn, it is essential to proceed systematically. The initial assessment is aimed at ruling out systemic disorders. Examination for abnormalities of deep tendon reflexes and ligament laxity helps consider peripheral causes.

If suspected, sepsis must be ruled out with blood, urine, and cerebrospinal fluid cultures. Additionally, obtaining a complete blood count, comprehensive metabolic profile, magnesium, and a drug screen. If the neonate is found to have hepatosplenomegaly or calcification on a head ultrasound, then a workup for congenital infection should be initiated. It includes toxoplasmosis, rubella, cytomegalovirus, herpes simplex, human immunodeficiency virus (TORCH) titers, urine cytomegalovirus studies, and Zika virus testing. To assess the central causes of hypotonia, a workup should be done to look for genetic and metabolic disease as a cause. In the presence of dysmorphic features or congenital malformations, a chromosome analysis with routine karyotyping or specific testing for fluorescence in situ hybridization (FISH) can aid in diagnosing certain diseases such as Down syndrome and PWS

Metabolic disorder screening is done when there is multisystemic involvement. Screening for carbohydrate and mitochondrial disorders with lactate and pyruvate levels may be done. Altered levels of plasma amino acids and urine organic acids may indicate an underlying amino acid disorder or organic acidemia. Acylcarnitine and total carnitine levels can be obtained for organic and fatty acid metabolism defects. More specific testing may be done for peroxisomal disorders with very long-chain fatty acids and plasmalogens. When peripheral hypotonia is suspected, a creatine kinase (CK) level should be taken. In muscular dystrophies, CK is typically very elevated (>10x normal).

Electrophysiologic studies can be used as a screening tool for peripheral causes of hypotonia. However, performing and interpreting in a neonate or a young infant may be difficult. They can differentiate among disorders involving nerves, muscle, or neuromuscular junctions. If CK is mildly elevated (<10x normal) and electromyography (EMG) is myopathic, then a muscle biopsy will be needed. Muscle biopsy with immunohistochemical staining and electron microscopy can help differentiate between muscular dystrophies and myopathies. Although an invasive procedure, it plays an important role in diagnosis and guiding further workup. If the EMG is neuropathic, then testing for spinal muscular atrophy (SMA), hereditary sensorimotor neuropathy, and Dejerin-Sottas syndrome should be done.

Decrement or facilitation of EMG would suggest the disease of the neuromuscular junction. Radiologic evaluation with magnetic resonance imaging (MRI) and computed tomography (CT) of the brain can aid in diagnosing various causes of central hypotonia. Structural changes, migration defects, brain stem defects (Joubert syndrome), and abnormal signaling defects in the white matter and brain stem can be seen in neuroimaging. Magnetic resonance spectrometry can be useful in diagnosing certain metabolic disorders.[1][5][8]

Treatment / Management

In general, the treatment is supportive and, most of the time, takes precedence over finding the underlying cause. It is tailored to the symptoms of the infant and may depend on the underlying cause. An interprofessional team approach leads to better outcomes for patients. Rehabilitation, nutritional, and respiratory support must be provided. In cases of central hypotonia other than hypoxic-ischemic encephalopathy, the involvement of a metabolic expert and a geneticist is essential. Occupational, speech, and physical therapy are beneficial and crucial in maximizing muscle function and preventing secondary anatomic deformities. Nutritional support is very important in these patients as they are often underweight and have various macro- and micronutrient deficiencies. Their requirements may increase during illness, and it must be addressed. In severe cases of chest muscle weakness, nasogastric or percutaneous gastrostomy tubes are needed for nutrition.[1][2][5]

Specific treatment can be provided in certain cases, such as Pompe disease, where early enzyme replacement therapy can significantly improve the outcome.[4] Recently, few treatments have been approved by the US Food and Drug Administration for SMA, although these are among the most expensive treatments available. Spinraza is a gene therapy that repairs the SMN2 gene. Zolgensma replaces the missing or defective SMN1 gene. While Spinraza and Zolgensma are given intrathecally, Risdiplam has recently been approved as oral therapy.[6][9] (B3)

Genetic counseling must be done for parents. Prenatal testing and testing for at-risk relatives must be offered whenever applicable. Parents must be actively involved from the beginning and should be educated about the disease.[2][5]

Differential Diagnosis

Central Hypotonia

Systemic diseases affecting the central nervous system are the most frequent cause of hypotonia in neonates. Congestive heart failure in an infant born with a congenital heart defect is a frequent cause of hypotonia in newborns. Since most of the energy is used in breathing and pumping the blood to the body, the infants have significant hypotonia and weakness. Strength is difficult to assess because of the lack of any voluntary effort by an acutely ill infant. Another common cause is sepsis, which often presents with hypotonia, which can sometimes be severe as well. Newborns who have suffered a hypoxic-ischemic insult present with depressed consciousness in the neonatal period along with hypotonia. As time progresses, the infant gains consciousness and has increased tone and hyperreflexia by the end of 2 to 3 months. Metabolic disorders also present with generalized hypotonia, but these infants commonly have an altered mental status. They may also appear septic, but the diagnosis is only made once the metabolic screen results are available.[8] Genetic and chromosomal causes account for a large number of causes of hypotonia. Numerous genetic syndromes can lead to hypotonia, and it can be difficult for a clinician to identify them without the help of a genetic expert. They present with central hypotonia, dysmorphic features, developmental abnormalities, and positive family history in most cases.[8]

Down syndrome (trisomy 21) is the most common chromosomal cause. Characteristic features include an up-slanting palpebral fissure, flat facial profile, single transverse palmar crease, and poor Moro reflex. Diagnosis can be confirmed with a high-resolution chromosome analysis or fluorescence in situ hybridization (FISH).[4][5]

PWS is among the differential diagnoses in the case of unexplained hypotonia in neonates. Most cases (65%-75%) are due to a lack of expression of genes inherited paternally on chromosome 15. About one-fourth of cases are due to maternal disomy 15 (when both chromosomes are inherited from the mother, and there is an absence of paternal-derived chromosome 15). Very few cases are caused by a defect in the genetic imprinting. Patients with PWS have feeding difficulty, hypotonia, and failure to thrive in early infancy. This is replaced by excessive appetite and obesity in late infancy and childhood.[10] Methylation analysis or a FISH can be used to make the diagnosis.[5]

Peroxisomal disorders result from mutations in any of the 12 PEX genes, the most common being the PEX 1 gene. These disorders can fall anywhere along the spectrum of severity. Zellweger syndrome is the most severe form, and infantile reflex is the least severe form.[4] They are inherited in an autosomal recessive manner. Patients usually present with significant hypotonia and poor feeding in the newborn period. The liver, kidneys, eyes, brain, bones, and adrenals are involved. Diagnosis is based on the levels of very-long-chain fatty acids, with elevated levels of C26 and C26:1. Additionally, there is an elevated ratio of C26/C22 and C24/C22, along with elevation in the plasma levels of pristanic acid and phytanic acid.[11][12]

Benign congenital hypotonia is a nonprogressive disorder of the neuromuscular system. It is commonly seen and is a diagnosis of exclusion. Muscle tone improves with age, but the patient often has delayed milestone achievement. History and physical examination are not suggestive of a neurologic or metabolic cause. Routine blood tests, including muscle enzyme results, are normal. It is associated with the risk of joint dislocations later in life, and parents must be counseled about it.[5]  

Pompe disease, a rare autosomal recessive disease, is caused by acid alpha-glucosidase deficiency. There is an accumulation of glycogen in the lysosomes in the heart and the skeletal muscle tissue. It can present as the classic infantile Pompe disease with less than 1% enzyme activity. It is seen in the neonatal period with marked hypotonia, failure to thrive, and hepatomegaly, which often leads to death within the first year of life due to cardiac or respiratory causes if untreated. The electrocardiogram shows a short P-R interval and a wide QRS complex, a characteristic finding. A definitive diagnosis is made by a muscle biopsy, which shows a lower acid maltase enzyme activity.[5] Enzyme replacement therapy is an approved treatment for infantile Pompe disease. Earlier treatment initiation has been associated with better outcomes.[4][13]  

Peripheral Hypotonia 

Motor Neuron Disease

Spinal muscular atrophy (SMA) is an autosomal recessive disease that involves the anterior horn cells in the spinal cord and motor nuclei of the brainstem. It is a progressive neuromuscular degenerative disorder that results in proximal muscle weakness and paralysis. There are 4 main types of SMA (SMA 1, SMA 2, SMA 3, and SMA 4), based on the age at which the disease presents (from pre- and perinatal to adulthood) and the maximum motor function achieved.[6][9] Clinical features include symmetric proximal muscle weakness, atrophy, tongue fasciculations, and decreased to absent reflexes. These patients are also at increased risk of aspirations and failure to thrive.[9] The weakness usually progresses to respiratory insufficiency and, eventually, death.[5] Patients have normal cognition regardless of the type.[4]

Neuromuscular Junction Abnormalities 

Congenital myasthenic syndromes are due to gene mutations responsible for the neuromuscular junction's structure and function.[2][4] The gene mutation results in impaired neuromuscular transmission.[14] Most of them are inherited in an autosomal recessive manner. It can present shortly after birth to early childhood and rarely by adulthood. The ocular, bulbar, and limb muscles spar cardiac and smooth muscles. Characteristic features include hypotonia, feeding difficulties, expressionless face, progressively weakening cry, ptosis, and respiratory problems that may progress to cyanosis and apnea.[2][4] Diagnosis is usually made with EMG showing abnormal compound action potential with repetitive low-frequency stimulation.[4] The patient's response to subcutaneous or intravenous injection of edrophonium chloride can also be used for diagnosis.[5]

The transient acquired myasthenic syndrome is seen in neonates born to mothers with myasthenia gravis. There are antibodies against the acetylcholine receptors in the mother, which passively transfer to the placenta and interfere with the neuromuscular transmission in the neonate. Symptoms are seen within 2 to 3 days of life and resolve within 2 to 4 weeks with complete recovery. The amount of antibody transferred across the placenta directly correlates with the severity of the symptoms. Symptoms include feeding difficulties, hypotonia, swallowing, and sucking difficulties, and they usually have a weak cry with an expressionless face. There may or may not be respiratory insufficiency. Treatment is symptomatic, which may include exchange transfusion, respiratory support as needed, and intravenous immunoglobulin (IVIg).[2][5]

Clostridium botulinum, an anaerobic, gram-positive bacteria, causes infantile botulism. The spores are present in the soil and are also present in honey. Ingestion of spores leads to the colonization of bacteria in the gut and leads to the release of a potent neurotoxin. The toxin produced is absorbed from the intestines. It acts on the presynaptic receptors, and the release of acetylcholine is inhibited. In foodborne botulism, the preformed toxin is ingested, whereas in infantile botulism, the toxin is produced in the gut. The toxin is continuously produced in infantile botulism as bacterial colonization of the large intestine. The affected age group is usually younger than 1 year, with a peak incidence at about 3 months. More severe symptoms are noticed in infants younger than 2 months of age. The first symptom to present is often constipation. Other characteristic features include cranial nerve involvement, respiratory problems, hypotonia, feeding difficulties, and decreased reflexes. The weakness appears to progress in a descending fashion. Diagnosis is made by isolating Clostridium botulinum bacteria or the botulinum neurotoxin from the stool. The prognosis is relatively good as recovery will be complete, but it takes several months. If proper care is provided, there is a less than 2% case-fatality rate. Treatment is mostly supportive care with special attention to pulmonary hygiene and nutritional support. Antibiotics are avoided as they are not known to have any benefit, and they may lead to lysis of bacteria in the intestines, releasing large amounts of toxins.[2][7]

Drug toxicity 

Aminoglycosides provide coverage against gram-negative bacteria and are commonly used in neonates and infants when there is a concern for sepsis and meningitis. They are potentially toxic and can cause renal toxicity, ototoxicity, and neuromuscular blockade. Gentamicin has been found to have maximum neuromuscular blocking action. The effects on the neuromuscular junction are greater in the case of preterm neonates due to immature renal function, which leads to higher levels of the drug in the serum. Clinical features include muscle weakness and hypotonia. Aminoglycosides must be avoided in patients with neuromuscular junction disorders such as infantile botulism and myasthenia-like syndromes.[2]

A magnesium level of more than 1.15 mmol/L (2.8 mg/dL) is hypermagnesemia in neonates. It is frequently seen in babies born to mothers who received treatment for eclampsia with magnesium sulfate. Clinical features include hypotonia, hypo/areflexia, respiratory depression, poor feeding, bradycardia, and ileus. Monitoring the magnesium level and providing supportive care are often sufficient.[2]  

Muscle disorders  

Congenital muscular dystrophy is an inherited disorder. The classification is based on the clinical features in the patients and certain biochemical defects. The presentation can vary from a mild disorder with survival into adulthood to a fatal disease with a poor prognosis. The 2 most common types are:

1. Congenital muscular dystrophy type 1A: Laminin-A2 is deficient in 30% to 40% of patients. Clinical features include peripheral hypotonia, joint contractures, delayed motor milestone achievement, kyphoscoliosis, and respiratory problems. The disease begins at an early age, during infancy or early childhood. Intelligence is normal in the majority of patients. Skeletal muscle biopsy would be significant for dystrophic changes. End-stage muscle disease has findings of increased muscle fibrosis.[4]
2. Ullrich congenital muscular dystrophy: Presents with torticollis, kyphoscoliosis, distal joint hyperelasticity, and proximal joint contractures. Physiotherapy may improve scoliosis and contractures. Intelligence is often normal. Follicular hyperkeratosis may be an additional finding in some cases. Diagnosis is achieved through genetic testing and biopsy of the skeletal muscle with immunohistochemical analysis.[4]

Congenital myopathies are a group of muscle diseases classified based on certain characteristic features. They are present at birth and usually have hypotonia, feeding problems, delay in milestone achievement, and muscle weakness.[4]

1. Central core or multi-mini core disease: Usually does not progress or progresses very slowly. It is associated with malignant hyperthermia because of the defective ryanodine receptor. A muscle biopsy shows type 1 muscle fibers lacking oxidative enzyme activity.[4]
2. Nemaline myopathy: Presents with peripheral hypotonia at birth, scoliosis, and muscle weakness. A high-arched palate and facial weakness are also noticed. 3 forms are inherited in an autosomal recessive manner, which includes the severe form seen in the neonatal period, the milder classic form, and the late-onset form.[4]
3. Myotubular myopathy: Mainly affects males. This should be suspected when a male has neonatal hypotonia, a positive family history of X-linked inheritance, macrocephaly, arachnodactyly, and cryptorchidism. The severe form presents with severe hypotonia, and patients often require respiratory support due to insufficiency. Prenatal history is significant for decreased fetal movements and polyhydramnios. Patients with the moderate form have a better prognosis. They achieve milestones earlier as compared to the severe form and mostly do not require respiratory support.[4]

Prognosis

The prognosis depends on the underlying etiology. In some cases, such as transient myasthenia and infantile botulism, there is complete recovery with minimal to no complications. Hypotonia in sepsis or due to other illnesses like congestive heart failure also improves once the disease is treated. Certain conditions, such as spinal muscular atrophy and Pompe disease (classic infantile type), can be fatal early in life. Having an interprofessional team approach toward the patient by providing rehabilitation services, nutritional support, and home care services and involving various specialists can alter the prognosis, leading to better outcomes.

Complications

Complications of hypotonia are usually secondary to the problems associated with it. Mortality is highest under the age of 1 year, and those who survive beyond 1 year age often have developmental delays.[15] Most patients require nutritional support and may develop various micro/macro-nutrient deficiencies. Those requiring pulmonary support are more prone to respiratory infections in general and may develop pneumonia frequently. In some diseases, patients who are wheelchair-bound are more prone to fractures, osteopenia, development of contractures, and pressure ulcers, even if adequate physical therapy is provided to them.[16]