Weakness Disorders

The causes of weakness are wide-ranging. Patients can present to medical attention after an acute change occurring over minutes, a subacute change over hours, or a chronic change over weeks to months. In all cases, a comprehensive evaluation can result in potentially lifesaving or function-preserving interventions. Acute-onset weakness is a neurologic emergency, and neurology consultation is generally advisable, if available.

Neurologic examination skills require reading and organized thinking as well as experiential learning. For this reason, a major focus of a neurology rotation is learning about developmentally appropriate neurologic examination under the guidance of faculty, senior residents, or both.

In this section, we provide an overview of the evaluation of weakness and hypotonia in infancy and highlight some classic clinical presentations and conditions that cause weakness.

• Targeted Diagnostic Workup of Weakness

• Hypotonia in Infancy

• Key Peripheral Nervous System Conditions That Can Present with Weakness

  • Infantile Botulism

  • Spinal Muscular Atrophy Type 1

  • Congenital Myasthenia Syndrome

  • Transient Neonatal Myasthenia Gravis

  • Myasthenia Gravis

  • Guillain-Barré Syndrome

  • Muscle Abnormalities

    • Duchenne Muscular Dystrophy

• Key Central Nervous System Conditions That Can Present with Weakness

  • Pediatric Stroke

  • Spinal Cord Injury

Targeted Diagnostic Workup of Weakness

Ideally, a targeted diagnostic workup tests hypotheses generated from the clinical evaluation. The history generates clues that help clinicians form hypotheses (e.g., a child’s leg weakness, sensory loss below a certain level, and change in bowel and bladder function are due to a spinal cord problem). The physical and neurologic examinations provide further evidence that may or may not support initial hypotheses.

• The primary goal of the examination is efficient identification of the cause of weakness and prompt initiation of treatment.

• A secondary goal is judicious use of medical resources to minimize risk to the child and cost to the health care system.

Localizing the lesion: The overarching diagnostic process is what neurologists call localizing the lesion. At a minimum and, in most cases, an achievable goal is to differentiate central (brain, brain stem, and spinal cord) from peripheral (nerve root, nerve, neuromuscular junction, muscle) sources (i.e., localizing the problem to the central nervous system [CNS] or the peripheral nervous system [PNS]). Highly skilled clinicians can often localize more specifically to one of the following levels of the nervous system:

• brain

• brain stem

• spinal cord

• anterior horn cell

• nerve root

• nerve

• neuromuscular junction

• muscle

Although localizing a lesion is complex, common patterns of presenting symptoms can help. The following table describes classic examples of presenting symptoms and examination findings that localize to CNS versus PNS sources, along with examples of associated diagnoses.

Neurology consultation: Without careful formulation and localization to allow for targeted workup, all patients could potentially undergo a full range of tests, including neuroimaging (MRI) of the brain and spine with angiography; spinal tap; electromyography and nerve conduction studies (EMG/NCS); edrophonium (Tensilon) test; imaging, biopsy of muscle, or both; and an expanding number of genetic tests. Obviously, such an extensive workup is costly, time-consuming, potentially harmful, and ill-advised because it could delay the appropriate diagnosis.

Therefore, neurology consultation prior to testing is often more cost-effective than the reverse — testing followed by consultation. Nonetheless, the primary physician’s evaluations, including a careful neurologic examination, can be extremely helpful in determining whether the neurologist’s findings are new or old or in evaluating a disease’s rate of progression.

Hypotonia in Infancy

Hypotonia in infancy — or floppy infant syndrome — is a diagnostic challenge because it can be a presenting sign of many systemic diseases and can be caused by disorders that affect any level of the nervous system, from brain to muscle. Although the differential diagnosis of hypotonia in infancy is broad, history and examination can considerably narrow the differential and inform focused diagnostic testing.

Clinicians are often asked to evaluate hypotonic infants, either in the neonatal intensive care unit (NICU), during the neonatal period, or later, during the first year of life, when concerns arise about the infant’s motor development. A thorough workup for infectious etiologies (e.g., sepsis) is required, especially in the neonatal period. Once infection has been ruled out, the overarching question that affects diagnostic decision-making is whether the cause of the hypotonia originates in the CNS or PNS. Problems in the brain are more often the cause of neonatal hypotonia than pathology at other levels of the nervous system.

Physical examination: Physical examination should include assessment of the infant’s general appearance. Dysmorphic features and organ dysfunction are suggestive of syndromic or metabolic causes of hypotonia. Down syndrome is a common cause of hypotonia.

Three key terms and considerations in the evaluation of hypotonia in infants are tone, posture, and strength:

• Tone is defined by the resistance of muscles to passive stretching. When tone is low, strength is not necessarily low. Generally, if a child is hypotonic but their strength seems preserved, the localization is central, not peripheral.

• Posture in the neonatal period is the amount of flexion and adduction in the limbs that is observable during the awake state. This posture is assessed relative to expected posture, based on the infant’s postconception age.

• Strength is the maximum contractile force or voluntary resistance to a movement.

History: History should start with details of the pregnancy, delivery, and postnatal period.

• Maternal risk factors: Most maternal risk factors signal a CNS cause. Maternal risk factors include:

  • maternal hypertension

  • suboptimal weight gain during pregnancy

  • chronic or acute medical diagnoses affecting the pregnant mother

  • illicit drug use

• Pregnancy and delivery: Breech position, decreased fetal movement, polyhydramnios, or joint contractures can indicate either central or peripheral causes of hypotonia. The following questions can be helpful in obtaining a thorough history:

  • Was adequate prenatal care received?

  • Were prenatal ultrasound findings normal?

  • Was fetal in utero movement normal?

  • Was the pregnancy associated with oligohydramnios or polyhydramnios?

  • Were there any toxic exposures or infections during pregnancy?

  • Was the infant born prematurely?

  • Was the infant delivered by cesarean section and if so, for what reason? (Failure to progress may indicate hypotonia in utero.)

  • Did the infant experience birth trauma (a risk factor for spinal cord injury)?

  • What were the infant’s Apgar scores?

  • Were any abnormalities noted on the newborn metabolic screen?

• Postnatal period: Infants born after a normal pregnancy and delivery and who have a normal newborn examination but develop hypotonia after the first few days of life should raise suspicion for inborn errors of metabolism. A thorough developmental history is important in children who present after the neonatal period and may provide clues to localization.

  • Examples:

    • In the neonatal period, disorders of the neuromuscular junction (see Myasthenia Gravis) may present with sucking and swallowing difficulties that worsen with repetition of a task (fatigable weakness).

    • Concurrent constipation in infants raises the suspicion for infantile botulism.

    • Several genetic disorders present with hypotonia, including Prader-Willi syndrome, which is characterized by feeding difficulty in infancy.

    • Isolated motor delay with normal social and language development decreases the likelihood of brain pathology.

Neurologic examination: The neurologic exam should support or refute the hypotheses generated by the history regarding whether the source of the problem is due to central or peripheral nervous system pathology (or both). If hypotonia is minimal, strength seems normal, and the baby is feeding and breathing normally, a watch-and-wait approach can be appropriate without testing or neurologic consultation. Key aspects of the examination that support CNS versus PNS pathology are shown in the table below.

• Mental status: Assessment of mental status during the neurologic examination is important. The symptoms of a very alert hypotonic infant with weakness sufficient to affect breathing and feeding are more likely to be associated with a peripheral cause (e.g., nerve root, nerve, neuromuscular junction, or muscle). Neurologic consultation should be obtained in all such infants. Infants with hypotonia and depressed mental status are more likely to have a disorder affecting the brain (e.g., a chromosomal abnormality, ischemic injury, or metabolic disease).

• Motor function: Evaluation encompasses assessment of bulk, tone, strength, and reflexes.

  • Muscle bulk is primarily evaluated by inspection. Attention should be paid to symmetry.

  • Extremity tone can be assessed by passive movement. Truncal tone is assessed with tests of vertical and horizontal suspension.

  • Strength can be assessed by observing movements for antigravity strength and symmetry. Determining whether low strength (versus hypotonia only) is present on examination can be challenging, but it is critical for guiding the diagnostic evaluation. Uncertainty is a good reason for neurologic consultation.

  • Deep tendon reflexes may provide important clues to localization but can require some experience to obtain and interpret. Hyperreflexia and clonus indicate a CNS etiology, while decreased or absent reflexes indicate a PNS etiology.

Examination of parents: If a mother displays symptoms of myasthenia gravis (e.g., fatigable ptosis), transient neonatal myasthenia may be the cause of her child’s hypotonia. The mother should be evaluated for grip myotonia and percussion myotonia if congenital myotonic dystrophy is suspected.

Diagnostic testing: History and physical examination should guide diagnostic workup for a hypotonic infant. If brain pathology is suspected and hypotonia is mild, a watch-and-wait approach may be reasonable.

• MRI: If hypotonia is more significant and associated with focal weakness, the first test should be a brain MRI. Suspicion of spinal cord injury should also prompt MRI of the spinal cord.

• Metabolic testing: Usually consists of lactate, pyruvate, ammonia, serum amino acids, and urine organic acids, and it may include screening for hypothyroidism if newborn metabolic screen has not yet been done. The role of metabolic tests is diminishing with the greater availability of rapid exome sequencing.

• Genetic analysis: Dysmorphic features should prompt genetic analysis, usually starting with chromosomal microarray.

  • Suspicion for Prader-Willi syndrome requires specific methylation testing.

  • Suspicion for congenital myotonic dystrophy requires special testing for CTG repeat expansions.

• Creatine kinase (CK): CK is easily obtained and can be helpful if disorders of the muscle are suspected.

• Electromyography (EMG), nerve conduction studies, and muscle biopsy: These tests are considered if a peripheral cause for weakness is suspected and CK is normal. However, rapid genetic testing for neuromuscular diseases may identify a specific peripheral cause faster.

Key Peripheral Nervous System Conditions That Can Present with Weakness

Infantile Botulism

Botulism is a rare neuromuscular condition resulting from toxins produced by Clostridium botulinum bacteria. Infantile botulism typically affects children younger than one year of age. This condition results when spores (typically found in honey, dust, or dirt) are ingested and multiply in the gastrointestinal tract, allowing toxin release into the bloodstream. Infants are thought to be more susceptible to the effects of the spores due to immature gut flora. This toxin disrupts the release of acetylcholine into the cleft, causing neurotransmission failure and flaccid paralysis.

Presentation: Infants with botulism typically present with hypotonia, descending flaccid paralysis, or both; bilateral cranial nerve palsies (e.g., ptosis, sluggishly reactive pupils, diminished gag reflex, and bifacial weakness); and constipation. Involvement of diaphragmatic muscles can lead to respiratory failure necessitating mechanical ventilation. Diagnosis is made by detecting botulinum toxin in the stool, although treatment should not be delayed while awaiting confirmation of diagnosis.

Treatment: Treatment with intravenous botulism immune globulin (Baby-IV) neutralizes free botulinum toxin. Early treatment is crucial for preventing progression of disease. Notably, this treatment prevents the progression of the disease but will not reverse the effects of the toxins that are already affecting neurotransmission. Ultimately, recovery occurs via regeneration of nerve terminals and motor end plates. Thus, symptoms that are already present prior to initiation of therapy will take weeks to months to resolve, and a full recovery should be expected. There should be no significant cognitive or long-term motor sequelae of botulism infection, unless severe complications have occurred (e.g., hypoxic brain injury from respiratory insufficiency).

(Source: Infant Botulism: Review and Clinical Update. Pediatr Neurol 2015.)

Spinal Muscular Atrophy Type 1

Spinal muscular atrophy (SMA) is a group of genetic disorders. SMA types 0-4 are autosomal recessively inherited conditions characterized by degeneration of alpha motor neurons. A mutation in the SMN1 gene is the most common cause of SMA. SMA is caused by homozygous mutations (typically, exonic deletions) in the SMN1 gene. The age of onset and severity of the phenotype is influenced by the copy number of SMN2 genes. Infants with SMA1 present typically before 6 months of age with profound weakness sparing the face and with intact cognition.

Diagnosis: Diagnosis is based on genetic testing. SMA testing is highly reliable and has been introduced in at least 32 states in the United States. However, SMA testing only identifies exon deletions and as a result approximately 5% of cases (due to point mutations) are not detected at birth. Prompt genetic testing is crucial in infants in whom this diagnosis is suspected.

Treatment: Disease-modifying genetic therapies are now available and highly effective, particularly if treatment is started early, and include nusinersen, risdiplam, and gene therapy. Multidisciplinary care, including pulmonary management and nutritional support, is critical.

Congenital Myasthenia Syndrome

Congenital myasthenia syndrome is caused by pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction.

Presentation: Clinical presentation is similar to that of autoimmune myasthenia gravis in older children and adults, with onset typically shortly after birth or within the first 2 years of life. In some subtypes, children may have severe exacerbations precipitated by fever or infection. Congenital myasthenia syndrome should be suspected in young children with fluctuating weakness that affects eyelids (ptosis) or extraocular muscles. Neonates may have multiple joint contractures (arthrogryposis multiplex congenita) resulting from lack of fetal movement in utero.

Diagnosis and treatment: A combination of laboratory testing (notably negative anti-acetylcholine receptor [anti-AChR] and anti-muscle-specific kinase [anti-MuSK] antibodies), electromyography (EMG), and genetic testing is typically used for diagnosis. Most children with congenital myasthenia syndrome benefit from acetylcholinesterase (AChE) inhibitors, although some variants are unresponsive.

Transient Neonatal Myasthenia Gravis

Approximately 10% to 20% of infants born to mothers with myasthenia gravis develop transient symptoms of myasthenia gravis due to transfer of maternal AChR antibodies to the fetus. The recurrence rate increases to approximately 75% among mothers with a prior affected infant.

Presentation: Symptoms present within the first hours to a few days after birth. Infants affected by transient neonatal myasthenia gravis have generalized weakness and hypotonia, often with bulbar weakness leading to poor swallowing and weak cry with preservation of deep tendon reflexes. Ptosis and ophthalmoplegia are less common. Respiratory muscle weakness may occur, and approximately 30% of affected neonates require mechanical ventilation.

Diagnosis and treatment: If the mother does not have known disease, diagnosis is made by evaluating the infant’s response to an AChE inhibitor, typically neostigmine. If the infant responds, neostigmine should be continued. Supportive care is important, and infants with transient neonatal myasthenia gravis may require tube feeds and mechanical ventilation. Most infants recover fully within 2 months.

Myasthenia Gravis

Myasthenia gravis is an antibody-mediated disease of the neuromuscular junction that causes fatigable weakness. In children, as in adults, it is generally an acquired condition caused by the production of autoantibodies that bind to the postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction. AChR antibodies account for 80% of cases of autoimmune myasthenia gravis. These antibodies target acetylcholine receptors on the postsynaptic part of the neuromuscular junction. When antibodies bind to the receptor, they accelerate degradation of the receptor and physically block synaptic transmission at the neuromuscular junction. Autoantibodies against muscle-specific kinase (MuSK) can also cause myasthenia gravis. MuSK antibodies initiate cell cycle arrest, inhibit cell proliferation, and downregulate genes that are important to the function of the neuromuscular junction, disrupting neuromuscular transmission. These mechanisms interfere with the ability of the nerve to activate the muscle.

Two other forms of myasthenia gravis also seen in children are inherited congenital myasthenia gravis and transient and neonatal myasthenia gravis (see Hypotonia in Infancy above).

Presentation: Most patients with juvenile myasthenia gravis present with fluctuating weakness that worsens throughout the day and after continuous activity. Extraocular muscles are usually affected first, and almost all children with juvenile myasthenia gravis have ptosis. Extraocular muscle weakness may be the only symptom in 15% of children and adolescents. If generalized weakness has not occurred within a year of presentation, it is unlikely to develop later. In addition to extraocular weakness, bulbar weakness is also very common. Weakness of bulbar muscles may cause difficulty chewing and swallowing, drooling, weak voice (hyponasal phonation), and dysarthria. Generalized weakness is usually more severe in proximal muscles. Importantly, respiratory muscles, including the diaphragm, may be affected and can lead to respiratory distress and death.

Examination: Diagnosis should be suspected after a careful history suggestive of fatigable weakness and demonstration of fatigable weakness on physical examination. On exam, weakness and muscle fatigability can often be elicited by asking a child to sustain actions for a period of 3 minutes and observing closely for fatigue. For example:

• Eyelid weakness: Ask the child to gaze upward at a target for 3 minutes and watch for ptosis.

  • If ptosis occurs, a simple bedside ice pack test involves applying an ice pack to the eyelids to help clarify if the ptosis is part of myasthenia gravis. The cold temperature reduces the breakdown of acetylcholine by acetylcholinesterase and can thereby increase the concentration of acetylcholine remaining at the synapse — reducing ptosis (improving lid strength).

• Proximal muscle weakness: Ask the child to maintain arms fully extended in horizontal position, and watch for fatigue in the deltoids causing the arms to drift down.

• Pharyngeal weakness: Ask the child to speak, and listen for a characteristic hyponasal sound; observe the child drinking through a straw.

Prompt assessment of respiratory function using forced vital capacity (FVC), negative inspiratory force (NIF), or both is critical in patients with a new presentation or exacerbation of diffuse weakness that can affect respiratory function. A useful bedside maneuver is the single-breath count test (see Guillain-Barré syndrome [GBS]).

Diagnosis:

• Antibody testing (AChR, MuSK, or both) usually confirms the diagnosis of myasthenia gravis. However, this laboratory result may not be available before treatment is needed.

• An edrophonium test (Tensilon test) can also be performed with appropriate neurocritical expertise and capability for resuscitation. Because edrophonium can cause a cholinergic crisis with severe bradycardia, the availability of atropine at the bedside is recommended. During a myasthenic crisis, infusing the acetylcholinesterase (AChE) inhibitor edrophonium can rapidly and transiently improve signaling at the neuromuscular junction and restore strength. This temporary increase in strength can often be fairly dramatic. Videotaping of the edrophonium test is advised for documentation purposes.

• Additional diagnostic tests include electromyography (EMG), which usually shows a decremental response to repetitive stimulation, and testing for serum antibodies. Thymus abnormalities are common in patients with myasthenia gravis, and a chest CT scan or MRI should be performed to evaluate for thymoma.

Treatment:

• First-line therapy for juvenile myasthenia gravis is AChE inhibitors, most commonly pyridostigmine.

• In chronic cases, immunomodulatory treatment can reduce or prevent crises of acute weakness and hospitalizations and improve strength and quality of life.

• High-dose glucocorticoid therapy has been shown to be beneficial for immunosuppression, but high-dose treatment should not be initiated in outpatients because up to 50% of patients can have transient deterioration that can result in death from respiratory failure.

• Children with diffuse generalized weakness and impending or actual respiratory failure should be admitted to the intensive care unit and treated with plasma exchange or intravenous immune globulin (IVIG) and receive supportive care.

• Long-term treatment with IVIG may also be utilized.

• Thymectomy should be considered.

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is a monophasic (usually), acute, immune-mediated polyneuropathy. GBS is a heterogeneous entity with a number of variant forms, including demyelinating (the most common) and axonal neuropathies. GBS is the most common cause of acute paralysis in previously healthy infants and children. Two-thirds of patients have a history of infection (in particular, campylobacter, cytomegalovirus [CMV], Epstein-Barr virus [EBV], mycoplasma pneumonia, influenza, and Covid-19), typically 2 to 4 weeks before the onset of symptoms. These infections are thought to trigger an immune response directed against peripheral nerve roots and axons or peripheral nerve myelin. GBS has been reported after receipt of the influenza vaccine; however, the risk of GBS following an influenza infection is several times greater than the risk associated with vaccination. Therefore, vaccination against influenza reduces GBS risk.

Presentation: Classically, GBS begins with paresthesia in the toes followed by symmetric leg weakness that typically ascends over hours to days to involve the arms, face, and in severe cases, the muscles of respiration. In children, particularly young children, back and leg pain, gait difficulty, and refusal to walk are the most common presenting symptoms.

In addition to weakness, autonomic dysfunction is common and dangerous in GBS. Autonomic symptoms can include bladder and bowel dysfunction, orthostatic hypotension, and most important, cardiac dysrhythmias.

Examination: On physical examination, children with GBS have symmetric or mildly asymmetric weakness with decreased or absent reflexes. Cranial nerves may be involved, especially in variant forms such as Miller Fisher syndrome (an acquired nerve disease that is considered a variant of Guillain-Barré syndrome), which is characterized by external ophthalmoplegia and ataxia along with muscle weakness and areflexia. It is important to monitor and assess respiratory function with either forced vital capacity (FVC) or negative inspiratory force (NIF). A useful bedside technique is the single-breath count test: ask the child to inhale deeply and count out loud as high as possible until he or she needs to take a breath. Generally, a child who cannot count to 20 in one breath is not safe for admission to the floor and should be admitted to the intensive care unit (ICU). The single-breath count test correlates with formally tested FVC and NIF. It is not sufficient to assess respiratory status with a pulse oxygenation sensor only.

Diagnosis: GBS is a clinical diagnosis, although testing can support the diagnosis. Supportive evidence includes albuminocytologic dissociation on cerebrospinal fluid (CSF; elevated CSF protein with a normal CSF leukocyte count), and nerve conduction studies demonstrating demyelination (in the most common, demyelinating form) or axonal dysfunction. If obtained, MRI with contrast may demonstrate enhancement of the cranial nerve roots, cauda equina, or spinal nerve roots. These studies are often normal in the first week or so of the disease; therefore, negative studies should be interpreted with caution.

Treatment: Any child with history and examination consistent with GBS should be hospitalized and treated. Respiratory capacity and autonomic symptoms should be monitored during the course of the illness. Symptoms progressively increase over 2 to 4 weeks, followed by gradual recovery over weeks to months.

• First-line treatment for GBS consists of plasma exchange or intravenous immune globulin (IVIG) to hasten recovery and improve outcome. Unlike many other neuroimmunologic diseases, glucocorticoids are not effective in treating GBS. Supportive care is also important, particularly when respiratory muscles are affected. Most children with GBS have an excellent recovery.

Muscle Abnormalities

Neuromuscular disorders include a wide range of diseases that affect the peripheral nervous system, including motor and sensory neurons, nerve roots, plexuses, peripheral nerves, neuromuscular junction, and muscles. Duchenne muscular dystrophy (DMD) is the most common pediatric muscle disease.

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe, progressive neuromuscular disease. DMD is an X-linked disorder, meaning that it primarily affects males; rarely, female carriers are affected due to skewed X inactivation. DMD is caused by mutations in the dystrophin gene on Xp21 that result in absent or insufficient dystrophin — a protein that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. Absence or dysfunction of dystrophin causes muscle cells to be fragile and prone to damage. Damaged muscle tissue is progressively replaced by scar tissue and fat.

Becker muscular dystrophy (BMD) is a variant phenotypic expression of gene defects in dystrophin, ultimately with a similar pathological mechanism, in which muscle cells are prone to damage but at a slower rate. In DMD, the dystrophin content is 0% to 5% of normal; in BMD, the dystrophin content is 5% to 20% of normal.

Presentation: Children with DMD often come to clinical attention due to gait disturbance, most commonly toe walking or frequent falls, often before 3 years of age. Less commonly, children with muscular dystrophies including DMD may present to neurology earlier for gross motor developmental delay. Some children are diagnosed prenatally due to a family history of the disease. Children with DMD are always symptomatic before age 5 years. In contrast, the age of onset of BMD is later.

Examination: Young children with DMD typically show mild proximal muscle weakness in the pelvic muscles, waddling gait, lumbar lordosis, Gowers sign, calf-muscle hypertrophy, tight ankle tendons, and decreased deep tendon reflexes. Short stature is also commonly observed.

(Source: Duchenne Muscular Dystrophy. BMJ 2020.)

Diagnosis: Early diagnosis is critical in the management of DMD. Initial testing in a child with muscular weakness should include:

• Serum creatine kinase: CK is elevated in DMD.

• Transaminases (elevated due to muscle injury): Occasionally, testing for other clinical problems reveals elevated transaminases that may be misattributed to liver disease.

• Confirmatory testing is by dystrophin gene deletion and duplication testing: 70% of patients with DMD have a single exon or multiexon duplication or deletion in dystrophin. If this testing is negative, the next step is next-generation sequencing, which can identify smaller deletions, duplications and insertions, and point mutations.

• Muscle biopsy can be performed if genetic testing does not confirm clinical suspicion of DMD. Muscle biopsy can also distinguish between DMD and BMD.

(Source: Diagnosis and Management of Duchenne Muscular Dystrophy, Part 1: Diagnosis, and Neuromuscular, Rehabilitation, Endocrine, and Gastrointestinal and Nutritional Management. Lancet Neurol 2018.)

Management: The mainstay of treatment for DMD is multidisciplinary supportive and preventive care and pharmacologic therapy with glucocorticoids.

• Guidelines address multiorgan involvement and complications, with specific recommendations for ongoing diagnostic assessments as well as interventions. Specialties commonly involved in the care of children with DMD include neurology, endocrinology, pulmonology, cardiology, physical medicine and rehabilitation, gastroenterology, nutrition, physical therapy, occupational therapy, speech therapy, psychology, and genetics. Multidisciplinary care is associated with improved survival of patients with DMD.

• Glucocorticoid therapy includes treatment with prednisone or deflazacort, both of which are specifically approved for use in DMD. Long-term glucocorticoid therapy includes several benefits:

  • Patients may maintain persistence of ambulation at a later age.

  • Patients may preserve upper-limb and respiratory function to a later age and avoid scoliosis surgery. Some evidence suggests that glucocorticoids delay the onset of cardiomyopathy and improve survival in patients with DMD. Uncertainty remains about which glucocorticoids are most effective, optimal doses, and the timing of initiation prior to age 5 years due to complications such as stunted growth. Deflazacort may cause less weight gain than prednisone.

• Consultation with neurology and cardiology regarding up-to-date recommendations for electrocardiograms and cardiovascular MRI are also warranted, given risks for cardiac dysfunction (cardiac complications are the most common cause of death in DMD).

• Emerging therapies include mutation-targeted therapies, including drugs that allow transcription to skip or bypass deletions, nonsense, or stop mutations.

Prognosis: The natural history of this disease is that symptoms progress with age, and on average, functional ability declines rapidly after 8-9 years of age. Children are usually wheelchair-bound by their early teenage years. Children with DMD may also have intellectual or learning disabilities. Orthopedic complications are common, and neuromuscular scoliosis develops in nearly all children with DMD. Patients with DMD are at high risk for respiratory complications due to progressive respiratory muscle weakness and eventually develop nocturnal hypoventilation followed by daytime respiratory failure. DMD also causes primary dilated cardiomyopathy and conduction abnormalities. New molecular therapies are changing the trajectory of this disease.

Key Central Nervous System Conditions That Can Present with Weakness

Pediatric Stroke

Stroke is among the top 10 causes of death in children and can result in significant disability. Diagnosis is often delayed because providers fail to consider stroke in children. The annual incidence of stroke is as frequent as 13 cases per 100,000 children older than one month of age and up to 40 cases per 100,000 births in neonates. Preterm infants have the highest rate, with up to 100 cases per 100,000 births.

Neonatal Stroke

Neonatal stroke (occurring between day of life 0-28) encompasses ischemic stroke and hemorrhagic stroke, often occurring within the first month of life.

Risk factors:

• cardiac disorders

• coagulation disorders

• trauma

• drug exposure

• perinatal asphyxia

• maternal and placental problems (including preeclampsia)

Presentation: Seizures are the most common presenting symptom of strokes in neonates. However, some infants with neonatal stroke do not present until they are older (around 6 months of age or later), when the family notices asymmetry in motor development or early handedness.

Diagnosis: MRI is the preferred imaging modality in neonates with suspected stroke.

Treatment: Acute care is supportive, and rehabilitation with physical and occupational therapy is often useful. In particular, constraint therapy, involving restraint of the better-functioning side, has been shown to increase use of the weak arm in patients with hemiplegic cerebral palsy.

Prognosis: Children with neonatal stroke may have long-term effects, including cerebral palsy, cognitive and sensory impairment, and epilepsy. The reported incidence of these outcomes varies considerably. Most children ultimately are able to walk, and most do not experience seizures past the neonatal period. Risk of recurrent stroke is low.

Stroke in Infants and Older Children

Acute treatment for ischemic stroke can prevent death and reduce disability. However, recognition of strokes in childhood in a timely manner remains extremely challenging. Rapid initiation of imaging protocols and consultation of neurology when stroke is suspected is critical.

Risk factors: The etiologies of stroke in childhood are highly variable and a cause remains unknown in approximately 30% of cases. Possible causes include:

• congenital heart disease

• sickle cell disease

• hypercoagulable states

• trauma

• vascular malformations (e.g., arteriovenous malformation)

• vasculitis

Presentation: Children with stroke generally present with focal deficits (e.g., acute weakness). Children may also present with more-generalized symptoms (e.g., 40% of children present with a headache). Any child with acute onset of a focal neurologic deficit (including unilateral weakness, facial droop, unilateral sensory loss, loss of vision, or speech changes) should be evaluated for stroke. Children with a first-time seizure with persistent focal deficit should also be evaluated for stroke, as should children with altered mental status and a known stroke risk factor. Stroke also has many mimics in childhood, including hemiplegic migraine and seizures with postictal paralysis. Stroke should always be ruled out before the other diagnoses are considered.

Diagnosis: A suggested diagnostic approach to ischemic stroke can be found here. Children with suspected stroke should be evaluated emergently. If the frontline clinician is concerned that a stroke has occurred, neurology, radiology, and if available, a stroke team should be alerted to facilitate acute evaluation with head CT or rapid MRI and vessel imaging as well as consideration for intervention, as in adult patients.

Treatment:

• Neurosurgery should be notified if hemorrhagic stroke is identified.

• Tissue plasminogen activator (tPA) is not FDA approved for use in children with ischemic stroke but can be used at the discretion of the treating physician.

• Children with sickle cell disease who present with stroke are treated differently, with hydration and simple transfusion or exchange transfusion. For more information, see Sickle Cell Disease in the Pediatric Hematology rotation guide.

Recurrence: Unlike neonates, who have a low risk of recurrent stroke, the risk for recurrent stroke in older children is between 15% and 18%. Once an acute stroke is identified and managed, the etiology of the stroke should be comprehensively evaluated, with studies including echocardiogram with bubble study to evaluate for patent foramen ovale (PFO). Evaluation for hypercoagulable states is also standard.

Secondary prevention depends on stroke mechanism, as follows:

• Anticoagulation with low-molecular-weight heparin (LMWH) is useful for long-term anticoagulation in children with risk of recurrent cardiac embolism, cerebral venous sinus thrombosis (CVST), and hypercoagulable states.

• Aspirin may be a reasonable option for children who do not have a high risk of recurrent embolism or a severe hypercoagulable disorder, but it should be considered on a case-by-case basis in consultation with neurology and hematology.

Spinal Cord Injury

Spinal cord injury is life-threatening in children and often results in severe disability. Adolescents and young adults (aged 15 to 25 years) have the highest risk of spinal cord injury. Younger children with spinal cord injury are more likely to have concurrent brain injury (see the section on Brain Injury in this rotation guide). Injury to the cervical spine accounts for more than 50% of spinal cord injuries. More than half of spinal cord injuries in children are the result of motor vehicle crashes. Other causes include sports-related accidents, falls, birth trauma, and child abuse. Children with some preexisting conditions, including genetic conditions that cause lax ligaments and spinal anomalies, are at higher risk of experiencing a spinal cord injury (e.g., atlantoaxial instability in up to 20% of children with Down syndrome).

Presenting symptoms and neurologic examination findings: Spinal cord injury often presents initially with a constellation of findings below the level of injury: weakness and flaccid hypotonia, decreased deep tendon reflexes, sensory loss, loss of bladder or bowel control, and autonomic dysfunction (spinal shock). Hyperreflexia and spasticity are characteristic of the chronic phase of injury.

When evaluating a child with a possible spinal cord injury, it is important to ascertain the mechanism of injury, whether any protective or restraining devices were used, and whether the child has any underlying medical problems. A complete trauma evaluation should be performed, including assessment of the spine for point tenderness, deformities, crepitus, or muscle spasm. A sensory exam should also be performed to elicit the level of sensory loss.

Spinal cord injuries may be complete or incomplete:

• In complete spinal cord injury, no motor or sensory function is preserved below the level of injury, including none in the sacral segments, S4-S5.

• In incomplete spinal cord injury, degrees of motor function vary in muscles controlled by levels of the spinal cord below the injury and sensation is partially preserved below the area of injury. Sensation is usually preserved to a greater extent than motor function because the sensory tracts are located in more-peripheral, less vulnerable, areas of the spinal cord.

Diagnosis: After the neurologic examination is complete, all children with suspected spinal cord injury should undergo plain radiographs of the spine. Although radiographs do not show the spinal cord, they can provide important information about bony alignment, vertebral fractures, and soft-tissue swelling around sites of injury. Extent of injury should be evaluated with MRI after acute management is provided.

Electrophysiological tests, including motor-evoked potentials and somatosensory-evoked potentials, may also be useful in identifying the level of spinal cord injury.

Management:

• Early immobilization is very important to prevent further injury and should start in the field with immobilization of the spine using a backboard.

• Hypotension should be avoided to prevent hypoperfusion of fragile areas of injured spinal cord.

• Glucocorticoids are often prescribed, although no evidence supports their use in acute spinal cord injury.

• Closed reduction may improve neurologic outcome in some cervical spine fractures with subluxation.

• Surgery is indicated in patients who have a progressive neurologic deficit in the presence of cord compression or a dislocation-type injury to the spinal column.

Long-term management of spinal cord injury includes supportive medical care (including bowel and bladder care and respiratory support if needed), rehabilitation (including therapies and adaptive equipment), and psychological support.

Prognosis: This is largely determined by the location of the spinal cord injury. In general, injuries with no identifiable MRI abnormality are associated with a better prognosis. Prognosis tends to be worse with high cervical lesions, hemorrhage, and long segments of edema on MRI. In general, injuries to the pediatric spine are frequently serious, with associated mortality rates reported to be as high as 59%, much higher than those noted among adults.