Motor Neuropathies and Peripheral Neuropathies



Motor Neuropathies and Peripheral Neuropathies


Anthony A. Amato



There is a vast number of neuromuscular diseases, some rare and others very common. This and the next chapter present the main ones in order of anatomical sequence: motor neurons, peripheral nerves, neuromuscular junctions, and muscles.


SPINAL MUSCULAR ATROPHIES


Background

A number of spinal muscular atrophies (SMAs) have been identified on the basis of age of onset, degree of physical impairment, life expectancy, mode of inheritance, and genetic localization. Most are childhood diseases and the most common, the infantile form, Werdnig-Hoffmann diseases, is the main consideration in the differential diagnosis of the “floppy infant.”



Pathophysiology



  • 1. SMA types 1 through 3 are allelic and caused by mutations in the spinal motor neuron gene (SMN gene) located on chromosome 5q13.


  • 2. Kennedy disease, or X-linked bulbospinal neuronopathy, is caused by mutations (expanded CAG repeats) in the androgen receptor gene.


Prognosis



  • 1. There are three major subtypes of autosomal recessive SMA:



    • a. SMA type I (SMA-1), commonly known as Werdnig-Hoffmann disease, manifests within the first 6 months of life and most affected children do not survive past the second year of life.


    • b. SMA type II (SMA-2), the chronic infantile subtype, presents between the ages of 6 and 18 months and is associated with survival into the second or third decade.


    • c. SMA type III (SMA-3), more frequently referred to as Kugelberg-Welander disease, manifests after the age of 18 months and can be associated with a normal life expectancy.


  • 2. Kennedy disease is another progressive form of SMA that may present in early or adult life (dependent on size of the mutation).


Diagnosis


Clinical Features



  • 1. The age of onset and severity of weakness are variable in the different forms of SMA.


  • 2. Most are characterized by generalized, symmetric proximal greater than distal weakness and atrophy, although there are rare forms associated with mainly distal extremity weakness.


  • 3. Fasciculations are often evident in extremity and bulbar muscles.


  • 4. Sensation is normal and deep tendon reflexes are reduced or absent.


  • 5. Oral pharyngeal weakness leads to dysphagia and aspiration pneumonia.


  • 6. Death is often due to respiratory failure related to diaphragmatic weakness.


Electrodiagnostic Features



  • 1. Sensory nerve conduction studies (NCS) are usually normal except in Kennedy disease in which the sensory nerve action potential (SNAP) amplitudes are reduced secondary to an associated sensory neuronopathy.


  • 2. Motor NCS are normal or have diminished compound muscle action potential (CMAP) amplitudes.


  • 3. Electromyography (EMG) shows increased insertional and spontaneous activity in the form of fibrillation potentials, positive sharp waves, and fasciculation potentials as well as large, polyphasic fast-firing motor unit action potentials (MUAPs) (i.e., decreased recruitment).


Laboratory Features



  • 1. Serum creatine kinase (CK) levels are normal or slightly increased.


  • 2. DNA testing is available for the most common forms (SMA types I-III, Kennedy disease).


Treatment



  • 1. There is no proven medical therapy to improve strength and function in patients with different forms of SMA and the main treatments are supportive but make a considerable difference in quality of life.


  • 2. Physical and occupational therapies are essential. Contractures develop in weak limbs; stretching exercises, particularly at the heel cords, iliotibial bands, and hips, should be started early.



  • 3. Bracing



    • a. The appropriate use of bracing assists children with SMA-2 and SMA-3 in ambulation and delays their dependence on a wheelchair.


    • b. Long-leg braces (knee-foot orthosis) may stabilize the knees and prevent the knees from buckling.


    • c. There may be some advantage to a lightweight, plastic knee-foot orthosis but it is difficult to keep the foot straight with such a device, whereas a high-top boot worn with double-upright braces, while more cumbersome, provides excellent stability. The choice depends on preferences of the patient and physician.


    • d. Night splints are used to maintain the feet at right angles to the leg to prevent ankle contractures, which will impair ambulation.


  • 4. Surgery



    • a. Reconstructive surgery of the legs often accompanies bracing to keep the legs extended and prevent contractures.


    • b. A simple way to maintain function in the legs with contractures in the iliotibial bands, hip flexors, and knee flexors is to perform percutaneous tenotomies of the Achilles tendons, knee flexors, hip flexors, and iliotibial bands. This procedure often allows a child who is becoming increasingly dependent on a wheelchair to resume walking.


    • c. Scoliosis may develop, leading to pain, aesthetic damage, and respiratory compromise. Spinal fusion is considered in children who experience discomfort due to greater than 35-degree scoliosis. Forced vital capacity (FVC) should generally be greater than 35% to minimize the risk of surgery.


  • 5. Respiratory failure



    • a. Respiratory muscle weakness may initially be managed by noninvasive methods (i.e., bilevel positive airway pressure [BiPAP]) and cough-assist devices. Consider BiPAP in patients with dyspnea or evidence of nocturnal hypopnea (e.g., frequent nocturnal arousals, morning headaches, excessive daytime sleepiness), particularly if the FVC is less than 50% of predicted.


    • b. Tracheostomy and mechanical ventilation should be discussed with patient and families and offered if it is their wish.


  • 6. Genetic counseling



    • a. Parents of children with SMA-1, -2, and -3 should be counseled that subsequent children have a 25% chance of being affected.


    • b. Kennedy disease is X-linked recessive; therefore, the next generation of males will not be affected but females will be obligate carriers.


    • c. Prenatal diagnosis is available for each of the SMA subtypes.


HEREDITARY SPASTIC PARAPLEGIA


Background



  • 1. The hereditary spastic paraplegias (SPGs) are a clinically and heterogeneous group of disorders characterized by progressive lower limb spasticity. There are over 30 genetically distinct subtypes.


  • 2. This group of disorders is subclassified by the pattern of inheritance, age of onset, and the presence of additional neurologic defects.


  • 3. The prevalence of SPG ranges from 2.0 to 4.3/100,000 in different populations.


Pathophysiology



  • 1. SPG may be inherited in an autosomal dominant, autosomal recessive, or X-linked nature (see www.genetests.com and Amato and Russell, 2008).



  • 2. Autosomal dominant inheritance accounts for approximately 70% of pure SPG (without additional neurologic features beyond progressive spasticity). Approximately 40% are due to mutations in the spastin gene and 10% are caused by mutations in the atlastin gene.


  • 3. Approximately 10% of the autosomal recessive mutations in the gene encoding for paraplegin (SPG7).


  • 4. X-linked SPG1 is caused by mutations in the gene encoding for the L1 cell adhesion molecule (L1CAM). X-linked SGP2 is caused by mutations in the proteolipid protein gene.


Prognosis

The disease is usually only slowly progressive and life expectancy is not affected in “pure” forms but may be reduced in “complicated” forms (see Clinical Features, below).


Diagnosis


Clinical Features



  • 1. Patients may be classified into “pure SPG,” if there is only spasticity and sensory involvement and “complicated SPG,” if there is associated optic atrophy, deafness, extrapyramidal disease, dementia, ataxia, peripheral neuropathy, or amyotrophy.


  • 2. Onset is variable: childhood-to-adult life.


  • 3. There is significant clinical and genetic heterogeneity between and within kinships with SPG.


Laboratory Features



  • 1. Cerebrospinal fluid (CSF) is usually normal, although increased protein is noted in some patients.


  • 2. Magnetic resonance imaging (MRI) scans may demonstrate atrophy of the spinal cord and occasionally, the cerebral cortex.


  • 3. Genetic testing is available for some forms of SPG (see www.genetests.com).


Treatment



  • 1. There are no specific medications to slow the progression of the disease.


  • 2. Treatment is supportive with physical and occupational therapies.


  • 3. Stretching exercises are important to prevent contractures.


  • 4. Braces and/or walkers may be necessary to stabilize the gait.


  • 5. Spasticity



    • a. Baclofen 5 mg by mouth (p.o.) three times a day (t.i.d.) to start. May increase up to 80 mg daily (20 mg four times a day [q.i.d.]) as tolerated and as needed.


    • b. Tizanidine 2 mg t.i.d. to start. May increase up to 12 mg t.i.d. as tolerated and as needed.


    • c. Diazepam 2 mg twice a day (b.i.d.). May increase up to 10 mg q.i.d. as tolerated and as needed.


    • d. Implanted pumps that deliver baclofen continuously to the intrathecal space are very effective but may migrate out of their proper location and have risks of infection, bleeding, and root pain.


AMYOTROPHIC LATERAL SCLEROSIS


Background



  • 1. Motor neuron disease, the general term for degeneration of upper motor neuron (UMN) and lower motor neuron (LMN), is often divided into four clinical
    syndromes that may reflect a spectrum of disease: Each subsyndrome can exist in pure form or progress to encompass features of both UMN and LMN disease and spread from one region of the musculature to adjacent areas.



    • a. Primary muscular atrophy is a degeneration of anterior horn cells without UMN involvement. One limb is typically affected first.


    • b. Adult-onset progressive bulbar palsy is the result of degeneration of bulbar nuclei and initially has little or no associated spinal anterior horn cell dysfunction or upper motor neuron signs.


    • c. Primary lateral sclerosis is a corticospinal tract degeneration, sparing the LMNs.


    • d. Amyotrophic lateral sclerosis (ALS) is the archetype of this class of disease and presents with variable combinations of the preceding abnormalities, that is, both UMN and LMN signs affecting the bulbar and somatic musculature.


  • 2. Progressive muscular atrophy accounts for roughly 10%, primary lateral sclerosis for only 1% to 3%, and progressive bulbar palsy for 1% to 2% of motor neuron disease. ALS is more common, with an incidence of 0.4 to 3.0/100,000 in all parts of the world and prevalence of 4 to 6 cases/100,000 population.


Pathophysiology



  • 1. Most cases of ALS are sporadic but as many as 10% are familial (FALS). Approximately 25% of cases of FALS are caused by mutations in the gene encoding copper/zinc (Cu/Zn) superoxide dismutase (SOD1). There are other less common inherited forms.


  • 2. The pathogenic basis of sporadic ALS is not known but theories abound.


Prognosis



  • 1. Sporadic ALS and FALS are clinically and pathologically similar.


  • 2. The course of ALS is relentless with a linear decline in strength with time. The median survival of the conventional type of disease is approximately 3 years but depends on adequacy of respiratory and nutritional support.


Diagnosis


Clinical Features



  • 1. Many patients exhibit only LMN signs or purely UMN signs early in the course of the disease.


  • 2. In the limbs, muscle weakness and atrophy usually begin asymmetrically and distally and then spread within the neuroaxis to involve contiguous groups of motor neurons.


  • 3. Bulbar involvement manifests initially as dysphagia or dysarthria that may have lingual, buccal, and spastic components.


  • 4. The El Escorial criteria for the diagnosis of ALS were developed for research purposes but are used as clinical guidelines:



    • a. A diagnosis of “definite ALS” requires the presence of UMN and LMN signs in the bulbar region as well as at least two of the three other spinal regions (i.e., cervical, thoracic, and lumbosacral).


    • b. “Probable ALS” is defined by the presence of UMN and LMN signs in at least two regions (some UMN signs must be rostral to the LMN deficits).


    • c. “Possible ALS” requires UMN and LMN signs in only one region, UMN signs alone in two or more regions, or LMN signs are rostral to the UMN signs.


    • d. Electrophysiologic criteria for definite LMN degeneration require (i) the presence of fibrillation potentials; (ii) large-amplitude, long-duration MUAPs; and (iii) reduced recruitment. EMG evidence of LMN degeneration in two muscles supplied by two different nerve roots and nerves in an extremity can substitute for clinical evidence of LMN loss in the extremity. Fulfilling the El Escorial criteria for definite or even probable ALS can be difficult even in patients with advanced disease.



Electrodiagnostic Features



  • 1. Sensory NCS are normal.


  • 2. Motor NCS may be normal or demonstrate reduced amplitudes secondary to atrophy. Distal latencies and conduction velocities are normal or reveal only slight slowing proportional to the degree of axonal loss.


  • 3. No evidence of conduction block or other features of primary demyelination.


  • 4. EMG demonstrates active denervation in the form of fibrillation potentials and positive sharp waves as noted above. The earliest abnormality is fasciculation potentials due to motor unit hyperexcitability/instability that occur prior to motor unit degeneration.


Treatment



  • 1. Riluzole



    • a. Two controlled trials have demonstrated that riluzole 50 mg p.o. b.i.d. extends tracheostomy-free survival by 2 to 3 months. Unfortunately, the studies did not find that riluzole improves muscular strength or quality of life.


    • b. Riluzole is thought to act by inhibiting the release of glutamate at presynaptic terminals.


    • c. Side effects include nausea, abdominal discomfort, and hepatotoxicity.


    • d. Check hepatic function tests every month for 3 months and then every 3 months while on riluzole. Hepatotoxicity is reversible once riluzole is discontinued.


  • 2. Supportive care



    • a. Despite that the lack of effective therapy to halt or reverse the progression of the disease, there are many therapeutic measures that improve the quality of life in patients with ALS and its variants.


    • b. Physical, occupational, nutritional, and respiratory therapy and psychologic support are essential. Patients are typically seen in clinic at least every 3 months by coordinated groups of therapists.


    • c. Evaluation by psychiatry, gastroenterology, pulmonary medicine, and social work is needed at appropriate junctures.


    • d. The neurologist is appropriately responsible for coordinating care and discussing end of life issues.


  • 3. Physical therapy



    • a. Stretching exercises, passive and active, to prevent contractures.


    • b. Assess gait and needs (i.e., cane, walker, wheelchair).


  • 4. Occupational therapy



    • a. Patients should be evaluated for adaptive devices (e.g., ball-bearing feeders) that may improve function.


    • b. The patient’s home should be evaluated for equipment needs.


  • 5. Dysarthria



    • a. Patients should be evaluated by a speech therapist.


    • b. Techniques may be given to help patient with articulation.


    • c. Patients may benefit from various speech augmentation devices and switch- or light-guided scanning computerized devices.


  • 6. Dysphagia



    • a. Because of the associated swallowing difficulties occurring with bulbar weakness, nutrition becomes impaired.


    • b. High-calorie and protein-concentrated supplementation should be added to diet.


    • c. When dysphagia is severe, a percutaneous endoscopy gastrostomy (PEG) is recommended. Some studies have demonstrated that nutrition by PEG or gastrojejunostomy improves quality of life and survival by a few months.



      • 1) Ideally, PEG placement should be done before FVC falls below 50% to reduce the risks of the surgical procedure.


      • 2) PEG placement does not prevent aspiration.



  • 7. Salivation



    • a. Drooling and hypersalivation can be a problem secondary to swallowing difficulties.


    • b. TCAs (e.g., amitriptyline 10-100 mg p.o. at bedtime [qhs]) have anticholinergic properties that can reduce secretions. In addition, patients not uncommonly have a reactive depression that may be helped by the addition of an antidepressant.


    • c. Scopolamine patches are useful if saliva is pooling and causing aspiration.


    • d. Other medications that can be used include



      • 1) Glycopyrrolate 1 to 2 mg p.o. b.i.d. to t.i.d.


      • 2) Benztropine 0.5 to 2.0 mg every day (qd)


      • 3) Trihexyphenidyl hydrochloride 1 mg qd to 5 mg t.i.d.


      • 4) Atropine 2.5 mg qd to 5 mg t.i.d.


    • e. Botulinum toxic injection into the salivary glands is beneficial in patients with refractory hypersalivation, but caution is advised as this may lead to increased pharyngeal weakness


  • 8. Thick mucus is reported by some patients, particularly when using the above medications to treat hypersalivation. Effective treatments include



    • a. Beta-blockers such as propranolol and metoprolol may help.


    • b. Acetylcysteine 400 to 600 mg p.o. qd in one to three divided doses or as a nebulizer treatment (3-5 mL of 20% solution every 3-5 hours).


  • 9. Spasticity



    • a. Baclofen 5 mg p.o. t.i.d. to start. May increase up to 80 mg qd (20 mg q.i.d.) as tolerated and as needed.


    • b. Tizanidine 2 mg t.i.d. to start. May increase up to 12 mg t.i.d. as tolerated and as needed.


    • c. Diazepam 2 mg b.i.d. May increase up to 10 mg q.i.d. as tolerated and as needed.


    • d. An implanted intrathecal pump may be very beneficial if oral medications are not adequate.


  • 10. Pseudobulbar affect



    • a. An antidepressant medication can be used, particularly in patients with underlying depression.


    • b. Amitriptyline 10 to 25 mg qhs increasing to 100 mg qhs as necessary.


  • 11. Constipation



    • a. Constipation may result from weakness of the pelvic and abdominal muscles, diminished physical activity, anticholinergic and antispasticity medications, and opioids.


    • b. Management includes increasing dietary fiber and fluid intake, adding bulkforming laxatives, and using suppositories or enemas as needed.


  • 12. Ventilatory failure



    • a. Most patients with ALS die as a result of respiratory failure; therefore, it is important to assess for symptoms of signs of respiratory impairment during each clinic visit.


    • b. Patients with forced vital capacities below 50% or those with symptomatic respiratory dysfunction are offered noninvasive ventilator support, usually BiPAP and at first, nocturnally.


    • c. Inspiratory and expiratory pressures are titrated to symptom relief and patient tolerability.


    • d. My experience has been that only a few patients desire tracheostomy and mechanical ventilation because it prolongs care, and is expensive and burdensome to the family. However, this is a decision that must be made by the patient. Tracheostomy needs to be offered to patients along with realistic counseling in regard to what this entails to the patient and the family.



    • e. Intermittent dyspnea and the anxiety that accompanies it may be treated with lorazepam 0.5 to 2 mg sublingually, opiates (e.g., morphine 5 mg), or midazolam 5 to 10 mg intravenous (IV) (slowly) for severe dyspnea.


    • f. Constant dyspnea can be managed with morphine starting at 2.5 mg q4h or continuous morphine infusion plus diazepam, lorazepam, or midazolam for associated anxiety.


    • g. Thorazine 25 mg every 4 to 12 hours rectally or 12.5 mg every 4 to 12 hours IV may alleviate terminal restlessness.


  • 13. Pain



    • a. Pain occurs in at least 50% of patients due to muscle cramps, spasticity, limited range of motion and contractures related to weakness, and skin pressure secondary to limited movement.


    • b. Careful positioning and repositioning of the patient, massage, physical therapy to help prevent contractures, antispasticity medications, antidepressants, nonsteroidal anti-inflammatory medications, and opioids may be used to treat pain.


  • 14. Psychosocial issues



    • a. Depression is not uncommon for patients and family members.


    • b. Patients and family members may benefit from local support groups.


    • c. Antidepressant medications.


ACUTE POLIOMYELITIS


Background



  • 1. Poliomyelitis is rare in developed nations due to routine use of the polio vaccine; however, not everyone has been vaccinated, thereby limiting “herd immunity.”


  • 2. A poliomyelitis-like illness occurs with other viruses (e.g., Coxsackie virus, West Nile virus).


  • 3. Rare cases are due to transmission of virus from inoculated child to nonimmunized adults via feces.


Pathophysiology



  • 1. The virus gains access to the host usually through oral or respiratory route. The virus proliferates and viremia ensues.


  • 2. The virus is taken up into the peripheral nervous system (PNS) via binding to receptors and the distal motor nerve terminals.


  • 3. Subsequent transport to the anterior horn cell in the spine occurs with inflammatory destruction of motor neurons in the spinal cord and brainstem.


Prognosis

Most infected individuals recover but to a variable degree. Late in life, some patients develop weakness and achiness in muscles that were previously affected (postpolio syndrome, see below).


Diagnosis


Clinical Features



  • 1. Most people (98%), especially children, experience a minor nonspecific systemic illness for 1 to 4 days: sore throat, vomiting, abdominal pain, low-grade fever, easy fatigue, and minor headache.


  • 2. The core neurologic illness is a febrile meningitis.


  • 3. A small proportion (2%) subsequently develop neck and back stiffness, fasciculations, and asymmetric or focal weakness involving the extremities or bulbar musculature.



  • 4. Following the initial illness and paralytic phase, recovery of function to varying degrees occurs over the ensuing 4 to 8 years.


Laboratory Features



  • 1. CSF examination usually reveals increased protein and pleocytosis initially consisting of both polymorphonuclear leukocytes and lymphocytes and then later predominantly lymphocytes. The cell count is usually less than 100 cells/mm3.


  • 2. Diagnosis may be confirmed by culture of the offending virus, although the sensitivity is low. Also acute and convalescent antibody titers can be obtained.


Electrophysiologic Findings



  • 1. Sensory NCS are normal.


  • 2. CMAP amplitudes may be reduced in patients with profound muscle atrophy.


  • 3. The motor conduction velocities and distal latencies are normal or slightly abnormal in those individuals consistent with the degree of large-fiber loss.


  • 4. EMG demonstrates reduced recruitment of MUAP early with positive sharp waves and fibrillation potentials within 2 to 3 weeks following the onset of paralysis.


Treatment



  • 1. There is no specific treatment other than supportive care.


  • 2. Respiratory status needs to be monitored closely and patient mechanically ventilated if necessary.


  • 3. Nutritional support should be given if patient is unable to eat on his or her own.


  • 4. Physical and occupation therapy are essential to improve function.


  • 5. An antiepileptic drug (AED) (e.g., gabapentin) or antidepressant medication can be used to treat associated pain that frequently accompanies the acute illness.


POSTPOLIOMYELITIS (POSTPOLIO) SYNDROME


Background

As many as 25% to 60% of patients with a history of paralytic poliomyelitis develop new neuromuscular symptoms 20 or 30 years after the initial acute attack.


Pathophysiology

It is thought that motor neurons unaffected by the poliomyelitis sprout to reinnervate previously denervated muscle fibers. These motor units that are increased in size may be under increased stress compared with normal motor units, leading to gradual degeneration over time in some.


Prognosis

The course and the symptoms are highly variable but as a rule, muscle weakness is slowly progressive, if at all.


Diagnosis


Clinical Features



  • 1. Patients with postpolio syndrome complain of progressive fatigue (80% to 90%), multiple joint pains (70% to 87%), and muscle pain (70% to 85%).


  • 2. Fifty percent to 80% of patients also develop progressive loss of strength and muscle atrophy. This progressive weakness usually involves previously affected muscles but muscles thought to be clinically spared at the time of the acute infection may at times become affected.



  • 3. Muscle cramps and fasciculations are also common.


Laboratory Features



  • 1. Unlike acute poliomyelitis, the CSF does not demonstrate pleocytosis or viral particles.


  • 2. Serum CK levels may be mildly elevated.


Electrophysiologic Findings



  • 1. Sensory NCS are normal.


  • 2. CMAP amplitudes may be reduced in patients with profound muscle atrophy.


  • 3. The motor conduction velocities and distal latencies are normal or only slightly abnormal proportionate to the degree of large-fiber loss.


  • 4. EMG demonstrates active denervation in the form of positive sharp waves and fibrillation potentials, fasciculation potentials, and reduced recruitment of long-duration, large-amplitude, polyphasic, and unstable MUAPs.


Treatment



  • 1. There are no specific therapies for postpolio syndrome.


  • 2. Treatment is supportive similar to that for other motor neuron disorders.


  • 3. Physical and occupational therapies can be beneficial.


  • 4. A recent double-blind, placebo-controlled trial demonstrated no benefit with pyridostigmine.


  • 5. Muscle pain may ease with TCA medications.


  • 6. Severe dysphagia, dysarthria, and respiratory weakness are treated as discussed in the section on Amyotrophic Lateral Sclerosis.


STIFF PERSON/STIFF LIMB SYNDROME


Background



  • 1. Moersch and Woltman were the first to describe 14 patients with the disorder, which they termed “stiff man syndrome.”


  • 2. Because the disorder is more common in women than in men, stiff person syndrome (SPS) has become the preferable name for the disorder.


  • 3. Some authorities have clinically subdivided SPS into three types:



    • a. Progressive encephalomyelitis with rigidity


    • b. Typical SPS


    • c. Stiff limb syndrome


  • 4. There is an increased incidence of insulin-dependent diabetes mellitus (IDDM) and various autoimmune disorders.


  • 5. There are reports of SPS associated with Hodgkin lymphoma, small cell carcinoma of the lung, and cancers of the colon and breast.


  • 6. SPS also can occur in patients with myasthenia gravis or thymoma.


Pathophysiology

SPS is an autoimmune disorder caused by antibodies directed against glutamic acid decarboxylase (GAD) and amphiphysin.


Prognosis

Patients develop progressive stiffness and rigidity of the trunk and spine. Immunomodulating therapies may modulate the course of illness, but most remain with significant and progressive disability.



Diagnosis


Clinical Features



  • 1. Progressive encephalomyelitis with rigidity is a rapidly progressive disorder associated with generalized stiffness, encephalopathy, myoclonus, and respiratory distress that is usually fatal within 6 to 16 weeks.


  • 2. Typical SPS



    • a. Characterized by muscular rigidity and episodic spasms involving truncal and limb muscles in the second to sixth decades of life. The limb-girdle area is usually affected first.


    • b. Typical involuntary large truncal spasms are elicited by engaging the muscles in use for walking and by loud noises or other forms of startle, but intense attacks of contractions can occur without these stimuli.


    • c. The stiffness and muscle spasms usually lead to gait impairment with occasional falls.


    • d. Patients may complain of dyspnea secondary to chest restriction due to stiffness in the thoracic muscles.


    • e. Paroxysmal autonomic dysfunction characterized by transient hyperpyrexia, diaphoresis, tachypnea, tachycardia, hypertension, pupillary dilation, and occasional sudden death may accompany the attacks of muscle spasm.


    • f. Approximately 10% of patients have generalized seizures or myoclonus.


    • g. Physical examination often shows exaggerated lumbar lordosis and paraspinal muscle hypertrophy secondary to continuous muscle contraction.


  • 3. Stiff limb syndrome is characterized by asymmetric focal rigidity and spasms in the distal extremities or face.


Laboratory Features



  • 1. Autoantibodies directed against the 64-kDa GAD are evident in 60% of primary autoimmune cases of SPS and sometimes become apparent only after repeated tests over months or years.


  • 2. Antibodies are directed against a 128-kDa presynaptic protein, amphiphysin, present in some patients with presumed paraneoplastic SPS.


  • 3. The CSF is often abnormal in patients with SPS demonstrating increased immunoglobulin G (IgG) synthesis, oligoclonal bands, and anti-GAD antibodies.


  • 4. Other autoantibodies and laboratory abnormalities are associated with concomitant autoimmune disorders (e.g., Hashimoto thyroiditis, pernicious anemia, hypoparathyroidism, adrenal failure, myasthenia gravis, systemic lupus erythematosus [SLE], and rheumatoid arthritis).


  • 5. Serum CK levels may be slightly elevated.


Electrophysiologic Findings



  • 1. Sensory and motor conduction studies are normal.


  • 2. EMG demonstrates normal-appearing MUAPs but firing continuously.


Treatment



  • 1. Symptomatic therapies



    • a. I usually initiate symptomatic treatment with diazepam 2 mg b.i.d. working up to a dosage of 5 to 20 mg three to four times a day. These patients tolerate, and can benefit from, huge doses of diazepines if introduced slowly.


    • b. Next I start oral baclofen 5 mg t.i.d., which is increased up to 20 mg q.i.d.


    • c. Intrathecal baclofen 300 to 800 μg/d may be tried if other agents are not tolerated or are unsuccessful.


    • d. Other symptomatic agents with purported benefit include clonazepam, dantrolene, methocarbamol, valproate, vigabatrin, gabapentin, and botulinum toxin injection.



  • 2. Various forms of immunotherapy may be tried to treat the underlying autoimmune basis and have been found to be beneficial in small trials.



    • a. I usually give a treatment trial of intravenous immunoglobulin (IVIG) 2 g/kg monthly for 3 months and, if this is effective, subsequently spread out the dosing interval or reduce the dosage tailored to patient responsiveness.


    • b. Plasma exchange (PE) and IVIG are useful in reducing spasms and the frequency of attacks, but they must be repeated at several weekly or monthly intervals and thus are not curative.


    • c. A trial of prednisone 0.75 to 1.5 mg/kg/d for 2 weeks, then 0.75 to 1.5 mg/kg every other day for 2 to 4 months is tried if IVIG is ineffective. If prednisone is beneficial, I taper the prednisone to the lowest dose that controls the symptoms. I do not use prednisone in patients with diabetes mellitus (DM).


    • d. Other immunosuppressive agents (e.g., rituximab, azathioprine, mycophenolate mofetil; Table 8-1) may be tried.









TABLE 8-1 Immunosuppressive and Immunomodulatory Therapies Commonly Used in Neuromuscular Disorders





















































































Therapy


Route


Dose


Side Effects


Monitor


Prednisone


p.o.


1.0-1.5 mg/kg up to 100 mg/d for 2-4 wk, then 100 mg every other day; single a.m. dose


Hypertension, fluid and weight gain, hyperglycemia, hypokalemia, cataracts, gastric irritation, osteoporosis, infection, aseptic femoral necrosis


Weight, blood pressure, serum glucose/potassium cataract formation


Methylprednisolone


IV


1 g in 100 mL/normal saline over 1-2 h daily or every other day for three to six doses


Arrhythmia, flushing, dysgeusia, anxiety, insomnia, fluid and weight gain, hyperglycemia, hypokalemia, infection


Heart rate, blood pressure, serum glucose/potassium


Azathioprine


p.o.


2-3 mg/kg/d single a.m. dose


Flulike illness, hepatotoxicity, pancreatitis, leukopenia, macrocytosis, neoplasia, infection, teratogenicity


Monthly CBC, liver enzymes


Methotrexate


p.o.


7.5-20 mg/wk; single or divided doses; 1 d/wk dosing


Hepatotoxicity, pulmonary fibrosis, infection, neoplasia, infertility, leukopenia, alopecia, gastric irritation, stomatitis, teratogenicity


Monthly liver enzymes, CBC; consider liver biopsy at 2 g accumulative dose



IV/IM


20-50 mg weekly; 1 d/wk dosing


Same as p.o.


Same as p.o.


Cyclophosphamide


p.o.


1.5-2 mg/kg/d; single a.m. dose


Bone marrow suppression, infertility, hemorrhagic cystitis, alopecia, infections, neoplasia, teratogenicity


Monthly CBC, urinalysis



IV


1 g/m2


Same as p.o. (although more severe), and nausea/vomiting, alopecia


Daily to weekly CBC, urinalysis


Chlorambucil


p.o.


4-6 mg/d single a.m. dose


Bone marrow suppression, hepatotoxicity, neoplasia, infertility, teratogenicity, infection


Monthly CBC, liver enzymes


Cyclosporine


p.o.


4-6 mg/kg/d split into two daily doses


Nephrotoxicity, hypertension, infection, hepatotoxicity, hirsutism, tremor, gum hyperplasia, teratogenicity


Blood pressure, monthly cyclosporine level, creatinine/BUN, liver enzymes


Mycophenolate mofetil


p.o


Adults (1 g b.i.d. to 1.5 g b.i.d.) Children (600 mg/m2/dose b. i.d. [no more than 1 g/d in patients with renal failure])


Bone marrow suppression, hypertension, tremor, diarrhea, nausea, vomiting, headache, sinusitis, confusion, amblyopia, cough, teratogenicity, infection, neoplasia


CBCs are performed weekly for 1 mo, twice monthly for the second and third month, and then once a month for the first year


Gamma-globulin


IV


2 g/kg over 2-5 d; then every 4-8 wk as needed


Hypotension, arrhythmia, diaphoresis, flushing, nephrotoxicity, headache, aseptic meningitis, anaphylaxis, stroke


Heart rate, blood pressure, creatinine/BUN


Rituximab


IV


375 mg/m2 weekly × 4 weeks or 750 mg/m2 (up to 1 g) × 2 weeks


Infusion related symptom complex (e.g., hypotension, rash, chills, urticaria, angioedema, bronchospasm), asthenia, headaches, nausea, vomiting, dizziness, infection


Periodic blood counts, avoid live vaccines


p.o., by mouth; IV, intravenous; IM, intramuscular; b.i.d., twice a day; CBC, complete blood count; BUN, blood urea nitrogen.


Modified with permission from Amato AA, Russell J. Neuromuscular Disease. New York: McGraw-Hill; 2008.




ISAACS SYNDROME (SYNDROME OF CONTINUOUS MUSCLE FIBER ACTIVITY)


Background



  • 1. The disorder is caused by hyperexcitability of the motor nerves, resulting in continuous activation of muscle fibers.


  • 2. Most patients develop this disease sporadically; however, several families with apparent autosomal dominant inheritance have been reported. Isaacs syndrome may occur in association with other autoimmune disorders (e.g., SLE, systemic sclerosis, celiac disease).


  • 3. Paraneoplastic neuromyotonia has been reported with lung carcinoma, plasmacytoma, and Hodgkin lymphoma.


  • 4. Isaacs syndrome may occur in patients with myasthenia gravis or thymoma.


  • 5. Generalized myokymia or neuromyotonia may complicate hereditary motor and sensory neuropathies (e.g., Charcot-Marie-Tooth disease [CMT]), acute or CIDPs, and autosomal dominant episodic ataxia.


Pathophysiology

Isaacs syndrome is an autoimmune disease caused by autoantibodies directed against voltage-gated potassium channels (VGKCs) located on peripheral nerves.


Prognosis

Most patients respond well to treatment.


Diagnosis


Clinical Features



  • 1. Isaacs syndrome usually occurs in adults but has been observed in the newborn.


  • 2. Patients manifest with diffuse muscle stiffness, widespread muscle twitching (myokymia), cramps, increased sweating, and occasionally CNS symptoms (e.g., confusion, hallucinations, insomnia).


  • 3. The myokymia is present continuously even during sleep.


  • 4. The muscle stiffness worsens with voluntary activity of the affected body segment.


  • 5. Patients may experience difficulty relaxing muscles following maximal contraction (i.e., pseudomyotonia).


  • 6. Some patients experience numbness, paresthesias, and weakness.


Laboratory Features



  • 1. Antibodies directed against VGKC are detectable in the serum and CSF.


  • 2. Patients may have other laboratory features associated with concomitant autoimmune diseases.


  • 3. CSF may demonstrate increased protein, increased immunoglobulins, and oligoclonal bands.


Electrophysiologic Findings



  • 1. After-discharges are often evident following standard motor conduction studies.


  • 2. EMG reveals continuous firing of MUAPs.


  • 3. The most common abnormal discharges are combinations of fasciculation potentials, doublets, triplets, multiplets, complex repetitive discharges, and myokymic discharges.



Treatment



  • 1. Various modes of immunomodulation appear to be beneficial in some patients, including plasmapheresis, IVIG, and corticosteroid treatment. I treat patients similar to those with CIDP, as discussed on pages 213-216.


  • 2. Symptomatic treatment with AEDs (e.g., phenytoin, carbamazepine, and gabapentin) may also be useful as well perhaps by decreasing neuronal excitability by blocking sodium channels.


TETANUS


Background



  • 1. Tetanus is a potentially life-threatening medical condition arising from the in vivo production of a neurotoxin from the bacterium Clostridium tetani.


  • 2. C. tetani produces tetanospasmin.


  • 3. It is estimated that more than 1 million people per year in the world demonstrate signs of clinical intoxication secondary to infections with C. tetani. About 150 cases of tetanus are noted each year in the United States by various governmental agencies.


Pathophysiology



  • 1. The bacteria or their spores gain access to the patient typically through a minor wound.


  • 2. In the central nervous system (CNS), tetanus toxin lyses the SNARE proteins necessary for the release of inhibitory neurotransmitters (glycine and γ-aminobutyric acid [GABA]).


  • 3. The result is hyperexcitability of motor neurons, leading to continuous motor unit firing, opisthotonus, and hyperreflexia.


  • 4. A form related to oral ingestion of the toxin by infants is known.


Prognosis



  • 1. The annual mortality rate due to this organism is variable, depending on the sophistication of health care delivery and immunizations.


  • 2. In Africa, the annual mortality rate is estimated at 28/100,000, while in Asia and Europe it is 15/100,000 and 0.5/10,000, respectively.


  • 3. In the United States, the mortality due to tetanus intoxication is less than 0.1/100,000.


  • 4. Worldwide, neonatal tetanus represents about 50% of the known cases with a mortality rate reaching 90%.


Diagnosis



  • 1. The clinical presentation of tetanus is subdivided into four major categories:



    • a. Local


    • b. Generalized


    • c. Cephalic


    • d. Neonatal


  • 2. Most patients initially complain of a feeling of increased “tightness” of the muscles adjacent to the wound in the affected extremity. There may be local pain.


  • 3. Both the pain and muscle stiffness can persist for months and remain localized with an eventual spontaneous dissipation.


  • 4. Most patients develop trismus (difficulty opening the mouth secondary to masseter muscle contraction).



  • 5. Progression to generalized tetanus with tonic contraction of either entire limbs or the whole body secondary to relatively mild noxious stimuli. The generalized whole-body muscle contraction, opisthitonus, consists of extreme spine extension, flexion and adduction of the arms, fist clenching, facial grimacing, and extension of the lower extremities. This generalized contraction may impair breathing.


  • 6. Neonatal tetanus is usually the result of an infected umbilical stump.



    • a. Several hours to days of feeding difficulty (poor suck), general irritability, and possibly less than normal mouth opening or generalized “stiffness.”


    • b. Infants born to immunized mothers rarely acquire tetanus as the immunity is passively transferred from mother to infant.


    • c. Once the massive whole-body contractions start, there is little doubt as to the diagnosis.


Treatment



  • 1. Patients with suspected tetanus intoxication should be hospitalized and evaluated for existent or impending airway compromise.


  • 2. Human tetanus immunoglobulin should be administered as well as adsorbed tetanus toxoid at a different site.


  • 3. The antibiotic of choice is metronidazole (500 mg IV every 6 hours for 7-10 days).


  • 4. If airway compromise is noted, there is a good chance that this situation will persist for some time and a tracheotomy should be considered.


  • 5. Benzodiazepines should be administered in large dosages intravenously to control muscle contractions. If this is ineffective, therapeutic neuromuscular blockade is warranted in addition to the benzodiazepines to maintain somnolence.


  • 6. If autonomic symptoms or signs develop, these should be treated immediately with appropriate medications.


  • 7. Physical and occupational therapies are usually needed during the recovery period to regain strength, endurance, and function.


GUILLAIN-BARRÉ SYNDROME AND RELATED ACUTE POLYNEUROPATHIES


Background



  • 1. There are three major subtypes of Guillain-Barré syndrome (GBS): acute in-flammatory demyelinating polyradiculoneuropathy (AIDP), acute motor and sensory axonal neuropathy (AMSAN), and acute motor axonal neuropathy (AMAN).


  • 2. The Miller Fisher syndrome (MFS) (ophthalmoplegia, ataxia, and areflexia) may share similar pathogenesis and can be considered a variant of GBS.


  • 3. Two-thirds of cases follow an infectious process by several days or weeks. There may be serologic evidence of recent infection with Campylobacter jejuni (32%), cytomegalovirus (CMV) (13%), Epstein-Barr virus (EBV) (10%), and Mycoplasma pneumoniae (5%). Many other cases follow a mundane febrile illness or immunization and about one-third have no evident precedent.


Pathophysiology



  • 1. GBS and its variants have an immune basis.


  • 2. The proposed mechanism is through molecular similarity between myelin epitopes and glycolipids expressed on Campylobacter, Mycoplasma, and other
    infectious agents, which precede attacks of GBS (molecular mimicry). Antibodies directed against these infectious agents cross-react with specific antigens on Schwann cells or the axolemma. Binding of these antibodies to target antigens on the peripheral nerve may lead to conduction block before there is structural nerve damage.


  • 3. A similar immunologic mechanism probably occurs in those few cases that follow immunization.


  • 4. In AIDP, inflammatory demyelination ensues and in AMSAN and AMAN axonal degeneration occurs.


Prognosis



  • 1. Progression is usually over 2 to 4 weeks. At least 50% of patients reach a nadir by 2 weeks, 80% by 3 weeks, and 90% by 4 weeks.


  • 2. Longer progression of symptoms and signs, particularly if over 8 weeks, is more consistent with chronic inflammatory demyelinating polyneuropathy (CIDP) (see below). Subacute progression over 4 to 8 weeks falls between typical AIDP and CIDP. The subacute disease is usually self-limited as in AIDP but responds to corticosteroids as in CIDP.


  • 3. Respiratory failure develops in approximately 30% of patients. Weakness of neck flexion and of shoulder abduction correlate to some extent with diaphragmatic failure.


  • 4. Following the disease nadir, a plateau phase of several days to weeks usually occurs. Subsequently, most patients gradually recover satisfactory function over several months. However, only about 15% of patients are without any residual deficits 1 to 2 years after disease onset and 5% to 10% of patients remain with persistent and variably disabling motor or sensory symptoms.


  • 5. The mortality rate is less than 5% with patients dying as a result of respiratory failure or respiratory distress syndrome, aspiration pneumonia, pulmonary embolism, cardiac arrhythmias, and sepsis related to secondarily acquired infections.


  • 6. Risk factors for a poorer prognosis (slower and incomplete recovery) are age greater than 50 to 60 years, abrupt onset of profound weakness, the need for mechanical ventilation, and distal CMAP amplitudes less than 10% to 20% of normal (see further on).


Diagnosis


Clinical Features



  • 1. Most patients initially have weakness, numbness, and tingling in the distal parts of the lower limbs that ascends to the proximal legs, arms, and face. Occasionally, symptoms begin in the face or arms and descend to involve the legs.


  • 2. Weakness is symmetric affecting proximal and distal muscles.


  • 3. Large-fiber sensory modalities (touch, vibration, and position sense) are more severely affected than small-fiber functions (pain and temperature perception).


  • 4. Patients with AMAN have no sensory signs or symptoms.


  • 5. Muscle stretch reflexes are reduced or absent.


  • 6. Autonomic instability is common with hypotension or hypertension and occasionally cardiac arrhythmias.


Laboratory Features



  • 1. Elevated CSF protein levels accompanied by no or a few mononuclear cells are evident in over 80% of patients after 2 weeks. Within the first week of symptoms, CSF protein levels are normal in approximately one-third of patients.


  • 2. In patients with CSF pleocytosis of more than 10 lymphocytes/mm3 (particularly with cell counts greater than 50/mm3), GBS-like neuropathies from Lyme disease,
    recent human immunodeficiency virus (HIV) infection, sarcoidosis, and poliomyelitis need to be considered.


  • 3. Elevated liver function tests (LFTs) are evident in many patients. In such cases, it is appropriate to evaluate the patient for viral hepatitis (A, B, and C), EBV, and CMV infections as triggers for the GBS.


  • 4. Antiganglioside antibodies, particularly anti-GM1 antibodies, may be found. GM1 antibodies correlate with C. jejuni infection but are not specific or prognostic, and there is no clinical need to order antibody tests.


Electrodiagnostic Features



  • 1. In AIDP, the NCS demonstrate evidence of a multifocal demyelination.



    • a. Sensory conductions are often absent, but when present, the distal latencies are markedly prolonged, conduction velocities are very slow, and amplitudes may be reduced. Of note, sural SNAPs may be normal when median, ulnar, and radial SNAPs are abnormal as AIDP is not a length-dependent neuropathy.


    • b. Motor conduction studies are most important for diagnosis: Distal latencies are prolonged and conduction velocities are very slow. The distal amplitudes may be normal or reduced secondary to distal conduction block. Conduction block or temporal dispersion may be apparent on proximal stimulation.


    • c. F-waves and H-reflexes are delayed or absent.


    • d. Prolonged distal motor latencies and prolonged or absent F-waves are often the earliest abnormal features. Early abnormalities of the distal CMAP amplitude and latency and of the F-waves reflect the early predilection for involvement of the proximal spinal roots and distal motor nerve terminals in AIDP.


    • e. Distal CMAP amplitudes less than 10% to 20% of normal are associated with a poorer prognosis.


  • 2. In AMSAN, the NCS demonstrate features of a primary axonopathy.



    • a. Sensory NCS are absent or show reduced amplitudes with normal distal latencies and conduction velocities.


    • b. Motor NCS likewise show absent or reduced amplitudes with normal distal latencies and conduction velocities.


  • 3. In AMAN, the NCSs are similar to those in AMSAN except that sensory conductions are normal.


Treatment



  • 1. There have been no treatment trials devoted solely to AMAN, AMSAN, or MFS. Nevertheless, treatments used for AIDP are given to all patients with GBS-related neuropathies with any substantial disability.


  • 2. Treatment is generally instituted when the patient is no longer able to walk. There have been, however, few abortive cases, because of which patients who are still able to walk but deteriorate in the second week due to illness are treated. Treatment as outlined below should begin as soon as possible, preferably within the first 7 to 10 days of symptoms.


  • 3. PE and IVIG have been demonstrated in prospective controlled trials to be equally effective in the treatment of AIDP.



    • a. The total plasma exchanged is 200 to 250 mL/kg of patient body weight over 10 to 14 days. The removed plasma is generally replaced with albumin.


    • b. Thus, a 70-kg patient would receive 14,000 to 17,500 mL (14-17.5 L) total exchange, which can be accomplished by four to six alternate-day exchanges of 2 to 4 L each.



  • 4. IVIG has replaced PE in many centers because it is easier to administer than PE, at least as effective, and more widely available. The dose of IVIG is 2.0 g/kg body weight infused over 5 days.


  • 5. There is no added benefit of IVIG following PE. Repeated courses of IVIG are sometimes used in patients who are not improving, but there is limited evidence for this approach.


  • 6. The mean time to improvement of one clinical grade in the various controlled, randomized PE and IVIG studies ranged from 6 days to as long as 27 days. Thus, one may not see dramatic improvement in strength in patients during the PE or IVIG treatments. There is no evidence that PE beyond 250 mL/kg or IVIG greater than 2 g/kg is of any added benefit.


  • 7. As many as 10% of patients treated with either PE or IVIG develop a relapse following initial improvement. In patients who suffer such relapses, we give additional courses of PE or IVIG.


  • 8. Respiratory care



    • a. Monitor FVC and negative inspiratory force (NIF) for signs of respiratory distress. FVC and NIF will decline prior to development of hypoxia and arterial blood gas.


    • b. Consider elective intubation once the FVC declines to less than 15 mL/kg or NIF to less than -20 to -30 cm H2O.


  • 9. Physical therapy



    • a. Careful positioning of patients is important to prevent bed sores and nerve compression.


    • b. Range-of-motion exercises are started early to prevent contractures.


    • c. As patient improves, exercises to improve strength, function, and gait are started.


  • 10. Supportive care



    • a. Deep venous thrombosis prophylaxis with pneumonic devices and heparin 5,000 units subcutaneously b.i.d.


    • b. Reactive depression is common in patients with severe weakness. Psychiatry consult can be beneficial.


  • 11. Neuropathic pain control.


  • 12. The issue of allowing immunizations for patients who have had GBS is not settled. In cases that have followed an immunization, repeat exposure is not endorsed. For most others, necessary vaccinations including those for influenza and pneumonia are appropriate after weighing the possible small risk of recurrence of GBS.


MILLER FISHER SYNDROME


Background



  • 1. In 1956, C. Miller Fisher reported three patients with ataxia, areflexia, and ophthalmoplegia. He related the syndrome to GBS.


  • 2. There is a 2 to 1 male predominance with a mean age of onset in the early forties.


  • 3. An antecedent infection occurs in over two-thirds of cases, the most common being H. influenzae and C. jejuni.


Pathophysiology



  • 1. Perhaps through molecular mimicry, autoantibodies directed against these infectious agents cross-react with neuronal epitopes.


  • 2. Anti-GQ1b antibodies can be detected in most patients with MFS.


  • 3. GQ1b is a ganglioside concentrated on oculomotor neurons, sensory ganglia, and cerebellar neurons.



Prognosis



  • 1. Clinical return of function usually begins within about 2 weeks.


  • 2. Full recovery of function is typically seen within 3 to 5 months.


Diagnosis


Clinical Features



  • 1. Diplopia is the most common initial complaint (39%); ataxia is evident in 21% at the onset.


  • 2. Ophthalmoparesis can develop asymmetrically but often progresses to complete ophthalomoplegia. Ptosis usually accompanies the ophthalmoparesis but pupillary involvement is less common.


  • 3. Other cranial nerves can also become involved. Facial weakness is evident in 57%, dysphagia in 40%, and dysarthria in 13% of patients.


  • 4. Some patients describe paresthesias of the distal limbs and less frequently, the face.


  • 5. Areflexia is evident on examination in more than 82% of patients.


  • 6. Mild proximal limb weakness can be demonstrated in the course of the illness in approximately one-third of cases. Some patients progress to develop more severe generalized weakness similar to typical GBS.


Laboratory Features



  • 1. Most patients with MFS have an elevated CSF protein without significant pleocytosis, but normal CSF protein does not exclude the diagnosis.


  • 2. Anti-GQ1b are an almost uniform finding but the diagnosis can be established on clinical grounds without using the test.


Electrophysiologic Findings



  • 1. The most prominent electrophysiologic abnormality in MFS is reduced amplitudes of SNAPs alone or out of proportion to prolongation of distal latencies or slowing of sensory conduction velocities.


  • 2. CMAPs in the arms and legs are usually normal.


  • 3. In contrast to limb CMAPs, mild-to-moderate reduction of facial CMAPs can be demonstrated in over 50% of patients with MFS.


  • 4. Blink reflex may be abnormal if there is facial nerve involvement. Reduced facial CMAPs coincide with the loss or mild delay of R1 and R2 responses on blink reflex testing.


Treatment



  • 1. There are no controlled treatment trials of patients with MFS.


  • 2. However, I treat patients with either IVIG 2 g/kg over 5 days or PE 250 mL/kg over 2 weeks, similar to GBS. Whether mild cases, particularly if walking is preserved, require treatment is uncertain.


IDIOPATHIC AUTONOMIC NEUROPATHY AND PURE PANDYSUTONOMIA


Background



  • 1. In many cases, this probably represents a postinfectious variant of GBS.


  • 2. There is heterogeneity in the onset, the type of autonomic deficits, the presence or absence of somatic involvement, and the degree of recovery.


  • 3. Approximately 20% of patients have selective cholinergic dysfunction and 80% have various degrees of widespread sympathetic and parasympathetic dysfunction.



Pathophysiology



  • 1. The disorder is suspected to be the result of an autoimmune attack directed against peripheral autonomic fibers or the ganglia.


  • 2. A subset of patients may have antibodies directed against calcium channels, which are present on presynaptic autonomic nerve terminals.


Prognosis



  • 1. Most patients have a monophasic course with progression followed by a plateau and slow recovery or a stable deficit.


  • 2. Although some patients exhibit a complete recovery, it tends to be incomplete in most.


Diagnosis


Clinical Features



  • 1. The most common symptom is orthostatic dizziness or light-headedness, occurring in about 80% of patients.


  • 2. Gastrointestinal involvement as indicated by complaints of nausea, vomiting, diarrhea, constipation, ileus, or postprandial bloating is present in over 70% of patients.


  • 3. Thermoregulatory impairment with heat intolerance and poor sweating is also present in most patients.


  • 4. Blurred vision, dry eyes and mouth, urinary retention or incontinence, and impotence also are often present.


  • 5. As many as 30% of patients also describe numbness, tingling, and painful dysesthesia of their hands and feet.


  • 6. Muscle strength is normal.


Laboratory Features



  • 1. The CSF often reveals slightly elevated protein without pleocytosis.


  • 2. There are no serologic or immunologic abnormalities in the serum.


  • 3. Supine plasma norepinephrine levels are normal, but standing levels are significantly reduced, when compared to normal controls.


Autonomic Testing



  • 1. Cardiovascular studies reveal orthostatic hypotension and reduced variability of the heart rate to deep breathing in over 60% of patients.


  • 2. An abnormal response to Valsalva maneuver can be demonstrated in over 40% of patients.


  • 3. Summated quantitative sudomotor axon reflex test (QSART) scores are abnormal in 85% of patients. Most patients have abnormal thermoregulatory sweat tests with areas of anhidrosis in 12% to 97% of the body.


  • 4. Gastrointestinal studies can demonstrate hypomotility anywhere from the esophagus to the rectum.


Electrophysiologic Findings



  • 1. Routine motor and sensory NCS and EMG are normal.


  • 2. Quantitative sensory testing may reveal abnormalities in thermal thresholds.


  • 3. Sympathetic skin response may be absent.


Treatment



  • 1. Conclusions regarding the efficacy of immunotherapy are limited because of the retrospective and uncontrolled nature of most reports. Trials of PE, prednisone, IVIG, and other immunosuppressive agents have been tried with variable success.



  • 2. I generally recommend a trial of IVIG 2 g/kg over 2 to 5 days.


  • 3. The most important aspect of management is supportive therapy for orthostatic hypotension and bowel and bladder symptoms.



    • a. Fluodrocortisone is effective at increasing plasma volume. Fluodrocortisone is administered only in the morning or in the morning and at lunch to avoid nocturnal hypertension. Initiate treatment at 0.1 mg/d and increase by 0.1 mg every 3 to 4 days until the blood pressure is controlled.


    • b. Midodrine, a peripheral α1-adrenergic agonist, is also effective and can be used in combination with fluodrocortisone. Midodrine is started at 2.5 mg/d and can be gradually increased to 40 mg/d in divided doses (every 2-4 hours) as necessary.


    • c. Gastrointestinal hypomotility can be treated with metaclopramide, cisapride, or erythromycin.


    • d. Bulking agents, laxatives, and enemas may be needed in patients with constipation. Urology should be consulted in patients with neurogenic bladders. Patients may require cholinergic agonists (e.g., bethanechol), intermittent self-catheterization, or other modes of therapy.


CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY


Background



  • 1. CIDP is an immune-mediated neuropathy characterized by a relapsing or progressive course.


  • 2. CIDP most commonly presents in adults with a peak incidence at about 40 to 60 years of age, and there is a slightly increased prevalence in men.


  • 3. The relapsing form has an earlier age of onset, usually in the twenties, compared to the more chronic progressive form of the disease.


  • 4. Relapses have been associated with pregnancy.


  • 5. The association of CIDP with infections has not been studied as extensively as in AIDP; however, an infection has been reported to precede only 20% of CIDP relapses or exacerbations.


Pathophysiology

The pathogenic basis of CIDP is autoimmune.


Prognosis



  • 1. Approximately 90% of patients improve with therapy; however, at least 50% have a subsequent relapse within the next 4 years and less than 30% achieve remission off medication.


  • 2. Patients treated early are more likely to respond, underscoring the need for early diagnosis and treatment.


  • 3. Progressive course, CNS involvement, and particularly, axonal loss have been associated with a poorer long-term prognosis.


Diagnosis


Clinical Features



  • 1. Most patients present with relapsing or progressive, symmetric proximal and distal weakness of the arms and legs.


  • 2. Although over 80% have both motor and sensory involvement, a few patients may have pure motor (10%) or pure sensory (5% to 10%) symptoms and signs.


  • 3. Almost all patients with CIDP have areflexia or hyporeflexia.



  • 4. Cranial nerve involvement can occasionally occur but is usually mild and not the presenting feature in CIDP.


Laboratory Features



  • 1. Elevated CSF protein (more than 45 mg/dL) is found in 80% to 95% of patients.


  • 2. CSF cell count is usually normal, although up to 10% of patients have more than 5 lymphocytes/mm3.


  • 3. Elevated CSF cell counts should lead to the consideration of HIV infection, Lyme disease, neurosarcoidosis, and lymphomatous or leukemic infiltration of nerve roots.


  • 4. As many as 25% of patients with CIDP or a CIDP-like neuropathy have an IgA, IgG, or IgM monoclonal gammopathy. A small number have one of the connective tissue diseases such as systemic lupus erythematosis.


  • 5. MRI with gadolinium may reveal hypertrophy and enhancement of the nerve roots and peripheral nerves.


Electrophysiologic Findings



  • 1. Research criteria for demyelination include slow motor nerve conduction velocity to less than 70% to 80% of the lower limit of normal, prolonged distal motor latencies to 125% to 150% of the upper limit of normal, prolonged F-wave latencies to 125% to 150% conduction block, and temporal dispersion.


  • 2. As many as 40% of patients with CIDP do not fulfill the rigid research criteria for demyelination and yet are responsive to immunotherapy. Treatment is not withheld in such patients if the diagnosis is considered likely on the basis of symmetric proximal and distal weakness in the arms and legs, diminished reflexes, and elevated CSF protein with appropriate nerve conduction findings.


Histopathology



  • 1. Nerve biopsies may reveal evidence of segmental demyelination and remyelination, endoneurial and perineurial edema, mononuclear inflammatory cell infiltrate in the epineurium, perineurium, or endoneurium that is often perivascular.


  • 2. However, nerve biopsies can reveal mainly axonal degeneration or may be completely normal.


  • 3. Nerve biopsy is not often performed and is necessary if patients do not have characteristic clinical and electrophysiologic features.


Treatment

Immunosuppressive and immunomodulatory therapies are used (see Table 8-1), albeit many have not been studied in a rigorous fashion. Randomized control trials have demonstrated efficacy of corticosteroids, PE, and IVIG in the treatment of CIDP. Patients may respond to one mode of treatment when other approaches have failed or the disease has become refractory. In most instances, repeated treatments over the years are required.



  • 1. IVIG



    • a. Several double-blind, placebo-controlled studies have demonstrated that IVIG is efficacious in CIDP and it has become the treatment of choice by many clinicians.


    • b. An observer-blinded, randomized trial of PE compared with IVIG found no difference in efficacy.


    • c. The dosage and interval between IVIG treatments needs to be individualized.


    • d. I begin IVIG treatment with a daily dose of 2 g/kg for 3 to 5 days.


    • e. Subsequently, I repeat IVIG 2 g/kg over 2 to 5 days every month for 2 months.


    • f. I then try to adjust the total dose and dosing interval, depending on the response. Some patients may get by with IVIG 1 g/kg every 2 to 3 months, whereas other patients need infusions every several weeks.



    • g. Serum IgA level may be assayed in patients prior to administering IVIG. Patients who are IgA-deficient may develop anaphylactic reactions to IVIG, which can contain some IgA.


    • h. In addition, IVIG should be used cautiously in patients with diabetes and avoided in those with renal insufficiency because it has been associated with renal failure secondary to acute tubular necrosis.


    • i. Many patients develop headaches (up to 50%), diffuse myalgias, fever, blood pressure fluctuations, and flulike symptoms. These side effects can be treated with prophylactic administration of hydrocortisone 100 mg IV, Claritin 10 mg p.o. or benadryl 25 to 50 mg p.o., and Tylenol 650 mg p.o. 30 minutes prior to each IVIG infusion. Also, lowering the rate of infusion should lessen side effects during the treatment.


    • j. A few patients actually develop aseptic meningitis. There are rare thrombotic complications (e.g., stroke and myocardial infarction), perhaps related to hyperviscosity.


    • k. Mild neutropenia is common, but this is rarely clinically significant.


  • 2. Corticosteroids



    • a. Corticosteroids are very effective in CIDP but have been used less since IVIG was introduced. When used, I usually initiate treatment with prednisone 1.5 mg/kg (up to 100 mg) daily for 2 to 4 weeks then switch to alternate-day treatment (e.g., 100 mg every other day [q.o.d.]).


    • b. Patients with diabetes may not be able to be treated with alternate-day prednisone secondary to wide fluctuations in blood glucose. In such cases, treat with equivalent dose of daily prednisone (i.e., 50 mg/d).


    • c. Patients are maintained on this dose of prednisone until their strength is normalized or there is a clear plateau in clinical improvement, which usually occurs by 6 months.


    • d. Subsequently, the dose of prednisone is slowly decreased by 5 mg every 2 to 3 weeks until they are on 20 mg q.o.d. At that point, I taper the prednisone no faster than about 2.5 mg every 2 to 3 weeks.


    • e. There are significant side effects related to long-term corticosteroid treatment including osteoporosis, glucose intolerance, hypertension, cataract formation, aseptic necrosis of the hip, weight gain, hypokalemia, and type 2 muscle fiber atrophy.


    • f. Obtain baseline bone density studies and repeat the study every 6 months while patients are receiving prednisone.


    • g. Start calcium (1,000 to 1,500 mg/d) and vitamin D (400 to 800 IU/d) for osteoporosis prophylaxis.


    • h. Bisphosphonates are effective in the prevention and treatment of osteoporosis. If dual-energy x-ray absorptiometry (DEXA) scans demonstrate osteoporosis at baseline or during follow-up studies, I initiate alendronate 70 mg per week. In postmenopausal women, I start alendronate 35 mg orally once a week as prophylaxis for osteoporosis. The long-term side effects of bisphosphonates are not known especially in men and young premenopausal women. Alendronate can cause severe esophagitis and absorption is impaired if taken with meals. Therefore, patients must be instructed to remain upright and not to eat for at least 30 minutes after taking a dose of alendronate.


    • i. Obtain baseline and periodic fasting blood glucose and serum electrolytes. Patients need to be instructed on a low-sodium, low-carbohydrate diet to avoid excessive weight gain, hypertension, and DM.


    • j. I recommend physical therapy and an exercise program in order to reduce these side effects.


    • k. To prevent pneumocystis infection, some clinicians introduce prophylactic trimethoprim-sulfmethoxizole if more than several months of corticosteroids are anticipated, but this is not a uniform approach.



  • 3. Plasma exchange



    • a. Two prospective, randomized, double-blinded, placebo-controlled trials using sham PE demonstrated its efficacy.


    • b. Response to treatment is transient, usually lasting only a few weeks. Thus, chronic intermittent PE or the addition of immunosuppressive agents is required.


    • c. I use PE, usually in combination with prednisone, in patients with severe generalized weakness because the response to PE may be quicker than that of using prednisone alone.


    • d. Approximately 200 to 250 mL/kg body weight is exchanged over five to six treatments during a 2-week period. Some patients will require more exchanges for maximum improvement to occur. Fibrinogen levels may be checked prior to each exchange to be certain that a bleeding diathesis has not occurred from removal of clotting factors.


    • e. Exchanges can be scheduled every 1 to 2 weeks and the duration between exchanges is gradually increased, sometimes with coadministration of low-dose prednisone.


    • f. I use PE alone in patients for whom we wish to avoid long-term prednisone (e.g., patients with poorly controlled DM or HIV infection) or in whom IVIG is contraindicated (e.g., patients with renal insufficiency).


    • g. I also use a trial course of PE in patients who do not fulfill all the criteria for CIDP or those who have an underlying condition making the diagnosis difficult (e.g., patients with diabetes and superimposed CIDP-like neuropathy). Because the response to PE is generally faster than the response to prednisone, one can often determine earlier whether such patients could have an immuneresponsive neuropathy.


  • 4. Azathioprine



    • a. I usually do not treat with azathioprine alone, but it is an option in patients who cannot be given prednisone, PE, or IVIG.


    • b. Azathioprine in combination with prednisone can be used in patients who are resistant to prednisone taper.


    • c. Begin azathioprine at a dose of 50 mg/d and gradually increase by 50 mg every week to a total dose of 2 to 3 mg/kg/d.


    • d. Approximately 12% of patients receiving azathioprine develop fever, abdominal pain, nausea, and vomiting, requiring discontinuation of the drug.


    • e. Other side effects include bone marrow suppression, hepatotoxicity, and risk of infection and future malignancy.


    • f. Monitor complete blood counts (CBCs) and LFTs every 2 weeks, while adjusting the dose of azathioprine and then every 3 months once the dose is stable.


  • 5. Mycophenolate mofetil



    • a. Small anecdotal reports suggest that some patients may benefit from mycophenolate mofetil.


    • b. I start at 1 g p.o. b.i.d. The dose can be increased by 500 mg per month up to 1.5 g p.o. b.i.d.


  • 6. Methotrexate



    • a. Small studies have suggested that methotrexate may be effective in CIDP. However, a recent double-blind, placebo-controlled trial of patients also receiving IVIG or prednisone did not demonstrate an added benefit.


    • b. For dosing recommendations, see Chapter 9.


  • 7. Rituximab



    • a. Rituximab is a monoclonal antibody directed against CD20 cell marker and will deplete B-cells for 6 months to a year or more. As B-cells are precursors to plasma cells, antibody production drops over time as well.


    • b. A few small reports have suggested that rituximab may be effective in patients with CIDP or demyelinating neuropathies associated with anti-MAG antibodies, although results have been mixed on the latter.



    • c. The dose of rituximab is 750 mg/m2 (up to 1 g) IV. The dose is then repeated in 2 weeks. This course is generally repeated every 6 to 9 months.


    • d. The main side effects are infusion reactions. Because rituximab depletes B-cells there is increased risk of infection. There have been a few reports of progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus (they had also been treated in past with other immunosuppressive agents).


  • 8. Cyclophosphamide

May 28, 2016 | Posted by in NEUROLOGY | Comments Off on Motor Neuropathies and Peripheral Neuropathies
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