Motor Neuropathies and Peripheral Neuropathies
Mohammad Kian Salajegheh
Anthony A. Amato
INTRODUCTION
There are a vast number of neuromuscular disorders, some rare and others more common. This chapter presents disorders of the motor neurons and peripheral nerves, with neuromuscular junction disorders and myopathies covered in Chapter 13.
SPINAL MUSCULAR ATROPHIES AND KENNEDY DISEASE
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 disease, is the main consideration in the differential diagnosis of the “floppy infant.” Kennedy disease is another hereditary disorder that leads to progressive degeneration of motor neurons.
Pathophysiology
1. SMA types 1 through 4 are allelic and caused by homozygous mutations in the survival motor neuron gene (SMN1 gene) located on chromosome 5q13, which produces the essential SMN protein. The severity of SMA is inversely correlated with copy numbers of another gene on this chromosome, called SMN2, which is a paralogous gene to SMN1. Due to exclusion of exon 7 on SMN2, it can only produce 10% functional SMN protein.
2. Kennedy disease, X-linked bulbospinal neuronopathy, or spinal and bulbar muscular atrophy (SBMA), is caused by mutations (expanded CAG repeats) in the androgen receptor gene (AR gene) located on chromosome Xq12, leading to degeneration of motor neurons and dorsal root ganglia cells. Repeat lengths of 38 to 68 are reported in patients.
Prognosis
1. The major subtypes of autosomal recessive SMA are as follows:
a. SMA type 1 (SMA-1), commonly known as Werdnig-Hoffmann disease, manifests within the first 6 months of life, with generalized weakness, hypotonia, and poor head control. Affected children are not felt to achieve the ability to sit unassisted, and most do not survive past the second year of life.
b. SMA type 2 (SMA-2), the chronic infantile subtype, presents between the ages of 6 and 18 months. Patients can sit unassisted but are never able to walk independently and generally survive into the second or third decade.
c. SMA type 3 (SMA-3), more frequently referred to as Kugelberg-Welander disease, manifests after the age of 18 months. The patients can walk unassisted at some point in their life and have a normal life expectancy.
d. SMA type 4 (SMA-4) represents less than 5% of SMA cases and is the mildest form of the disease. It is similar to SMA-3, but the onset is in adulthood.
2. Kennedy disease is another progressive form of motor neuron disease. Onset usually occurs in the mid-40s, in a range of 18 to 64 years (depending on the size of the mutations).
Diagnosis
1. Clinical features of SMA types 1 to 4
a. The age of onset and severity of weakness are variable in the different forms of SMA.
b. Most are characterized by generalized, symmetric proximal greater than distal weakness and atrophy, although there are rare forms associated with mainly distal extremity weakness (distal-SMA is not discussed in this chapter in detail; see reference Brain 2023:146;806-822.)
c. Sensation is normal and deep tendon reflexes are reduced or absent.
d. Death is often caused by respiratory failure related to diaphragmatic weakness, in more severe forms.
2. Clinical features of Kennedy disease
a. Fasciculations are often evident in extremity muscles.
b. Bulbar manifestations, including dysarthria and nasal speech, prominent tongue and facial muscle fasciculations
c. There are signs of mild androgen insensitivity, such as gynecomastia, testicular atrophy, and reduced fertility.
d. Oropharyngeal weakness may lead to dysphagia and aspiration pneumonia.
Electrodiagnostic Features
1. Sensory nerve conduction studies (NCS) are usually normal except in Kennedy disease in which the sensory nerve action potential (SNAP) amplitudes may be reduced secondary to an associated sensory neuronopathy.
2. Motor NCS are normal but may have diminished compound muscle action potential (CMAP) amplitudes, in distal forms.
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) (ie, decreased recruitment).
4. Grouped discharges may be seen in facial muscles in Kennedy disease.
Laboratory Features
1. Serum creatine kinase levels are normal or slightly increased.
2. DNA testing is available for the most common forms (SMA-1 to SMA-4, Kennedy disease, and some of the distal SMAs).
Treatment
1. Gene therapy for SMA
a. Nusinersen (FDA approved in 2016): Antisense oligonucleotide (ASO) that increases the amount of full-length, functional SMN protein by allowing for
inclusion of exon 7 in the SMN transcript (encoded by the SMN2 gene). Administered intrathecally at a dose of 12 mg per administration, initially with three loading doses at 14-day intervals, followed by a fourth loading dose after another 30 days, and then once every 4 months as maintenance dose. Side effects reported in trials include lower respiratory infection and constipation in patients with infantile-onset SMA, and pyrexia, headache, vomiting, and back pain in patients with later-onset SMA. Due to the potential risk for thrombocytopenia, coagulation abnormalities and renal toxicity, testing is required at baseline and before each dose.
b. Onasemnogene abeparvovec (FDA approved in 2019): gene therapy for patients of all SMA types of less than 2 years of age. Delivers human SMN1 cDNA through AAV9 vectors, transducing motor neurons cells of the brain and spinal cord to produce SMN protein. Administered as a one-time intravenous dose of 1.1 × 1014 vector genomes per kilogram of body weight. Starting 1 day prior to infusion, systemic corticosteroids equivalent to oral prednisolone of 1 mg/kg body weight are given daily for 30 days, and then tapered off slowly, based on the patient’s liver function. Side effects reported in trials include elevated liver aminotransferases and vomiting, and it carries a boxed warning for serious liver injury and acute liver failure. Liver function, platelet counts, and troponin-I levels need to be monitored prior to infusion and periodically for at least 3 months later.
c. Risdiplam (FDA approved in 2020): ASO with action similar to nusinersen. Administered as oral solution with daily dose of 0.15 mg/kg (age <2 months); 0.2 mg/kg (age 2 months to < 2 years); 0.25 mg/kg (age >2 years and weighing <20 kg); and 5 mg (age >2 years and weighing 20 kg or more). Side effects reported in trials for all patients include fever, diarrhea, and rash. In addition, or infantile-onset SMA, upper respiratory tract infection, lower respiratory tract infection, constipation, vomiting, and cough were reported.
d. No gene therapy approved for Kennedy disease.
2. Physical and occupational therapies are essential for all patients. 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, although 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 ankles, 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 because of high degrees of scoliosis.
5. Ventilatory failure
a. Ventilatory muscle weakness may initially be managed by noninvasive methods (ie, bilevel positive airway pressure [BiPAP]) and cough-assist devices. Consider BiPAP in patients with dyspnea or evidence of nocturnal hypopnea (eg, frequent nocturnal arousals, morning headaches, excessive daytime sleepiness), particularly if the FVC is less than 50% of the 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 (SMA-1 to SMA-4) 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 (HSP) are a clinically and heterogeneous group of disorders characterized by progressive lower limb spasticity. There are more than 80 genes described with 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 HSP ranges from 2.0 to 4.3/100,000 in different populations.
Pathophysiology
1. HSP may be inherited in an autosomal dominant, autosomal recessive, X-linked or maternally inherited (mitochondrial) manner (see https://www.ncbi.nlm.nih.gov/books/NBK1509/: Hereditary Spastic Paraplegia Overview by Peter Hedera, MD, PhD, FACMG, in GeneReviews).
2. Autosomal dominant inheritance accounts for approximately 75% to 80% of patients with HSP. Mutations in the SPAST gene encoding for spastin (SPG4) accounts for 40% and mutations in the ATL1 gene encoding for atlastin (SPG3A) accounts for 10% to 15% of all autosomal dominant HSP.
3. Autosomal recessive inheritance accounts for approximately 20% to 25% of HSP cases and is a heterogeneous group with continuously expanding numbers of newly identified genes. Mutations in CYP7B1 gene (SPG5A) accounts for 7.3% and mutations in the SPG7 gene encoding for paraplegin (SPG7) accounts for 5% of autosomal recessive HSP.
4. X-linked HSP cases are rare and only account for 1% to 2% of all individuals affected with HSP.
Prognosis
The disease is usually only slowly progressive, and life expectancy is not affected in “pure” forms but may be reduced in “complicated” forms.
Diagnosis
Genetic testing is available for many of the HSPs, now mostly in the form of panels covering a large number of genes.
Clinical Features
1. Patients may be classified into “pure HSP,” if there is only spasticity and sensory involvement, and “complicated HSP,” 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 HSP.
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 most forms of HSP.
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.
e. Botulinum A and B toxin injections
6. Urinary urgency
a. Oxybutynin 5 mg (2.5 mg in elderly) PO b.i.d-t.i.d. to start and maximum 5 mg q.i.d.
b. Intra-bladder injections with botulinum toxin.
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. Progressive 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 UMN signs.
c. Primary lateral sclerosis causes corticospinal tract degeneration, while 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 different parts of the world and prevalence of 4 to 6 cases/100,000 population.
3. 10% to 15% of patients with ALS may fulfill diagnostic criteria for frontotemporal dementia.
Pathophysiology
1. Most cases of ALS are sporadic, but as many as 10% are familial amyotrophic lateral sclerosis (FALS). More than 20 genes have been identified, with the most common causes in the United States and Europe being mutations in the C9ORF72 (40%), SOD1 (15%-20%), TARDBP, FUS, FIG4, and ANG genes. There are also other less commonly inherited forms that may have autosomal dominant, autosomal recessive, or X-linked inheritance (see http://alsod.iop.kcl.ac.uk/for up to date information on FALS genes).
2. A positive family history of ALS, dementia, or onset at a young age should raise the possibility for FALS. The absence of a positive family history does not exclude a diagnosis of FALS, due to the possibility of de novo mutations or poor penetration in the prior generation.
3. The pathogenic basis of sporadic ALS is not known but theories abound, including abnormal processing of RNA and alterations in protein stability and degradation, inflammation and infection, excitotoxicity, cytoskeletal and mitochondrial abnormalities, and others.
Prognosis
1. Sporadic ALS and FALS are clinically and pathologically similar for the most part, with some variation based on the type of genetic mutation and disease onset.
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 in 1994 and later revised (“revised” El Escorial criteria) in 1998. Although they have been proposed for research, they have also been used as clinical guidelines:
a. “Clinically 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 (cervical, thoracic, and lumbosacral).
b. “Clinically 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. “Clinically possible ALS” requires UMN and LMN signs in only one region, UMN signs alone in two or more regions, or LMN signs rostral to the UMN signs.
d. Electrophysiologic criteria for definite LMN degeneration require (1) the presence of fibrillation potentials; (2) large-amplitude, long-duration MUAPs; and (3) reduced recruitment.
e. Fulfilling the El Escorial criteria for definite or even probable ALS can be difficult even in patients with advanced disease.
f. There should be an absence of electrophysiologic, pathologic, and neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic findings
5. The Awaji-Shima Consensus Recommendations in 2008 proposed that evidence of LMN degeneration could be derived from either the clinical exam or needle EMG; two muscles supplied by two different nerve roots and nerves in an extremity, or single muscle in the bulbar or thoracic region. They also proposed for fasciculation potentials to be able to substitute for the presence of fibrillation potentials; however, only in the presence of other abnormalities.
6. To further simplify diagnosis, improve sensitivity and address issues concerning inter-rater reliability of prior diagnostic categories, the “Gold Coast criteria” were proposed in 2019. Studies comparing these criteria with the prior ones have shown greater sensitivity and slightly improved specificity for the Gold Coast Criteria, requiring the following:
a. Progressive motor impairment documented by history or repeated clinical assessment, preceded by normal motor function, AND
b. Presence of upper and lower motor neuron dysfunction in at least one body region (with upper and lower motor neuron dysfunction noted in the same body region if only one body region is involved) OR lower motor neuron dysfunction in at least two body regions, AND
c. Investigations excluding other disease processes (may include NCS and needle EMG, MRI, or other imaging; fluid studies of blood or CSF; or other modalities as clinically necessary).
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/ongoing denervation (fibrillation potentials and positive sharp waves), as well as chronic reinnervation (large-amplitude, long-duration motor unit action potentials with reduced recruitment) changes in multiple muscles of the regions examined (muscle innervated by same roots but different nerves). Per the Awaji criteria, fasciculations potentials are considered indicative of acute/ongoing denervation in muscles demonstrating evidence of chronic denervation.
Other Diagnostic Work Up
1. Testing to determine the presence of FALS or alternate diagnoses, with presentations similar to ALS, are important.
2. Genetic testing.
a. Genetic testing for SOD1 and C9ORF72 should be considered in all patients, given approved genotype-specific therapies or possibility for inclusion in clinical trials, respectively.
b. Broader testing with multigene panels should be considered in all patients with a positive family history of ALS (unless the gene has already been identified) or disease onset at a young age.
c. It is important for testing to be done under the supervision, and through, a genetic counselor or a physician knowledgeable about FALS given the gravity of a positive test, with potential psychologic, economic, and familial implications, as well as prognostic implication of various mutations and correct interpretation of the meaning of variants of unknown significance.
3. Neuroimaging.
a. Magnetic resonance imaging (MRI) is the preferred imaging study unless it is contraindicated.
b. Brain imaging is important to exclude brain pathology, in particular when there is bulbar or upper motor involvement.
c. Spine imaging should be considered at the levels above where there is upper motor neuron involvement (to exclude spinal cord pathology) and at the levels with lower motor neuron involvement (to exclude root involvement).
4. Laboratory testing, lumbar puncture and muscle biopsy are not required for the diagnosis of ALS but should be used to exclude alternate diagnoses with presentations similar to ALS, when suspicion exists (see Table 11-3 in Neuromuscular Disorders, 2nd Edition by Amato and Russell in references).
Treatment
1. Riluzole (FDA approved in 1995)
a. Two randomized controlled trials 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. Hepatic function needs to be checked every month for 3 months and then every 3 months while on riluzole. Hepatotoxicity is reversible once riluzole is discontinued.
2. Edaravone (FDA approved in the IV form in 2017 and oral form in 2022)
a. An initial randomized controlled trial in ALS patients was unable to show statistically significant benefit for function, using the revised ALS functional rating scale (ALSFRS-R) score, after 24 weeks with intravenous edaravone. Given the demonstration of a greater treatment effect in a subgroup of patients (definite or probable ALS, scores of 2 or better on all items of the ALSFRS-R, FVC of 80% or higher and disease duration of 2 years or less at entry), another trial was conducted targeting this subgroup. This second randomized control trial of 24 weeks, showed a smaller decline in function, based on ALSFRS-R, for the edaravone group, and an open-label follow-up also showed continued benefit out to 48 weeks.
b. Intravenous edaravone: The initial cycle is given as 60 mg IV daily for 14 days followed by 14 days drug-free. Subsequent cycles are given as 60 mg IV daily for 10 days out of 14 days, followed by 14 days drug-free periods.
c. Edaravone oral follows the same dosing cycle but given as 105 mg/5 mL orally/nasogastric tube daily, instead of IV.
d. Edaravone is a free radical scavenger believed to prevent motor neuron degeneration by reducing oxidative stress.
e. The most common reported side effects of edaravone are injection-site contusion, gait disturbance, and headache. Fatigue is also reported with oral forms. Both forms may cause allergic reactions including hives, rash, and shortness of breath, in particular in those with sulfite sensitivity (sodium bisulfite is an ingredient of edaravone).
3. Tofersen – limited to patients with ALS due to SOD1 mutations (SOD1-ALS) (FDA-approved in 2023)
a. Although an initial phase 1/2 trial of intrathecal tofersen injection showed lowered levels of the SOD1 protein in cerebral spinal fluid of SOD1-ALS patients, and confirmed by a larger phase 3 trial, the latter failed to demonstrate improvement in the ALSFRS-R score (its primary outcome measure) over 28 weeks, beyond placebo. It did, however, demonstrate reduction in bloodstream neurofilament light levels, felt to be reasonably likely to predict a clinical benefit in patients. This led to its FDA approval under an accelerated approval pathway. A follow-up study using 12 months of data from the phase 3 trial, and an open label extension, reported slower decline of ALSFRS-R, vital capacity, and grip strength, in all SOD1-ALS patients who received tofersen, in particular those with earlier initiation.
b. Tofersen is an antisense oligonucleotide that binds to SOD1 mRNA, leading to its degradation and reduced synthesis of SOD1 protein. Although the exact mechanisms of motor neuron degeneration by mutated SOD1 gene is not known, toxic gain of function has been considered to be the most likely mechanism in SOD1-ALS, and lowering its concentration a potential therapeutic target.
c. Tofersen is given intrathecally (by lumbar puncture) at a dose of 100 mg (15 mL), once every 14 days for three doses, followed by once every 28 days for maintenance therapy.
d. The most common side effects include injection site pain, headache, fatigue, arthralgia, myalgia and increased cerebrospinal (brain and spinal cord) fluid white blood cells and rarely increased intracranial pressure.
4. Supportive care
a. Despite 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 psychological 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.
5. Physical therapy
a. Stretching exercises, passive and active, to prevent contractures.
b. Assess gait and needs (ie, cane, walker, wheelchair).
6. Occupational therapy
a. Patients should be evaluated for adaptive devices (eg, ball-bearing feeders) that may improve function.
b. The patient’s home should be evaluated for equipment needs.
7. 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.
8. 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 feeding tube is recommended. Some studies have demonstrated that nutrition by percutaneous endoscopic gastrostomy or gastrojejunostomy improves the quality of life and survival by a few months.
1) Ideally, feeding tube placement should be done before FVC falls less than 50% to reduce the risks of the surgical procedure.
2) Feeding tube placement does not prevent aspiration.
9. Salivation
a. Drooling and hypersalivation can be a problem secondary to swallowing difficulties.
b. Tricyclic antidepressants (TCAs) (eg, 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 mg every day (qd)
3) Trihexyphenidyl hydrochloride 1 mg qd to 5 mg t.i.d.
4) Atropine 0.5 to 2 mg qd to t.i.d.
e. Botulinum toxin injection into the salivary glands is beneficial in patients with refractory hypersalivation, but caution is advised because this may lead to increased pharyngeal weakness.
f. Radiation therapy
1) In patients refractory to other measures, external beam radiation therapy to the caudal parotids and submandibular glands has proven effective.
2) Both short-term and long-term side effects have been reported (including dry mouth, mucositis, taste change, and skin reaction).
10. Thick mucus is reported by some patients, particularly when using the earlier medications to treat hypersalivation. Effective treatments include
a. β-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).
11. 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 baclofen pump may be beneficial if oral medications are not adequate.
12. Pseudobulbar affect
a. A combination of dextromethorphan (20 mg) and quinidine sulfate (10 mg) has been shown to be effective in a randomized trial. Side effects include dizziness, nausea, and somnolence but can be lessened by starting at 1 tablet qhs for 7 days followed by twice-a-day dosing.
b. Antidepressant medications, such as selective serotonin reuptake inhibitors and TCAs, can be used particularly in patients with underlying depression.
13. 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 bulk-forming laxatives, and using suppositories or enemas as needed.
14. Ventilatory failure
a. Most patients with ALS die as a result of respiratory failure; therefore, it is important to assess for symptoms or signs of ventilatory impairment during each clinic visit.
b. Patients with forced vital capacities less than 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. Our experience has been that only a few patients desire tracheostomy and mechanical ventilation because it prolongs care and is expensive and can be 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 (eg, 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 every 4 hours (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.
15. Pain
a. Pain occurs in at least 50% of patients because of 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.
16. 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 may need to be used.
ACUTE POLIOMYELITIS
Background
1. Poliomyelitis is rare in developed nations because of 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 (eg, Coxsackievirus, West Nile virus).
3. Rare cases are caused by 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 (post-polio syndrome).
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 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. Acute and convalescent antibody titers can also 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 on, 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) (eg, gabapentin) or antidepressant medication can be used to treat associated pain that frequently accompanies the acute illness.
POST-POLIOMYELITIS (POST-POLIO) 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 post-polio syndrome complain of progressive fatigue (80%-90%), multiple joint pains (70%-87%), and muscle pain (70%-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 creatine kinase 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 post-polio syndrome.
2. Treatment is supportive similar to that for other motor neuron disorders.
3. Physical and occupational therapies can be beneficial.
4. Double-blind, placebo-controlled trials demonstrated no benefit with either pyridostigmine or modafinil in reducing fatigue.
5. Muscle pain may ease with TCA medications.
6. Severe dysphagia, dysarthria, and respiratory weakness are treated as discussed in the section on ALS.
STIFF PERSON SPECTRUM DISORDERS
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) became a preferable name for the disorder.
3. Due to the broad spectrum of presenting signs and symptoms these disorders are being considered under the umbrella of SPS spectrum disorders (SPSD). Although varying opinions exist about how best to classify these conditions, the following phenotypes are proposed:
a. Classic SPS – most common ˜70% of SPSD.
b. Stiff limb syndrome or partial SPS.
c. SPS plus – 12% to 30% SPSD.
d. Progressive encephalomyelitis with rigidity and myoclonus (PERM) – some include PERM under SPS plus.
e. Pure cerebellar ataxia – some do not consider cerebellar ataxia as part of SPSD.
4. There is an increased incidence of insulin-dependent diabetes mellitus and various autoimmune disorders.
5. Approximately 5% of SPSD are associated with Hodgkin lymphoma, small cell carcinoma of the lung, and cancers of the colon and breast. A paraneoplastic process should be considered in older patients and within 5 years of disease onset.
6. SPSD can also occur in patients with myasthenia gravis or thymoma.
Pathophysiology
SPS is an autoimmune disorder caused by antibodies directed against glutamic acid decarboxylase (GAD) and amphiphilic.
Prognosis
Patients develop progressive stiffness and rigidity of the trunk and spine, in addition to other issues based on their phenotype. Immunomodulating therapies may modulate the course of illness, but most remain with significant and progressive disability.
Diagnosis
Clinical Features
1. Classic 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 because of 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.
2. Stiff limb syndrome is characterized by asymmetric focal rigidity and spasms in the distal extremities, torso, or face.
3. SPS-plus present similar to classic SPS with the addition of findings of brainstem and cerebellar involvement (including ocular motor dysfunction, dysphagia, dysarthria, nystagmus, and ataxia).
4. PERM is a rapidly progressive disorder associated with generalized stiffness, encephalopathy, myoclonus, and respiratory distress that is usually fatal within 6 to 16 weeks.
5. Pure cerebellar ataxia findings of cerebellar involvement (including incoordination, ataxia, poor manual dexterity, dysarthria, ocular motor dysfunction, nystagmus) without classic SPS musculoskeletal findings.
Laboratory Features
1. Autoantibodies directed against the 65-kDa GAD are evident in 60% to 80% of primary autoimmune cases of SPS and sometimes become apparent only after repeated tests over months or years. The levels are not felt to be correlated with disease severity.
2. Antibodies directed against a 128-kDa presynaptic protein, amphiphysin, present in some patients with presumed paraneoplastic SPS.
3. Other antibodies have been reported against: GABAa receptor, glycine receptor (in particular in PERM), GABAa receptor-associated protein and gephyrin.
4. The CSF is often abnormal in patients with SPS demonstrating increased immunoglobulin G (IgG) synthesis, oligoclonal bands, and anti-GAD antibodies.
5. Other autoantibodies and laboratory abnormalities are associated with concomitant autoimmune disorders (eg, Hashimoto thyroiditis, pernicious anemia, hypoparathyroidism, adrenal failure, myasthenia gravis, systemic lupus erythematosus [SLE], and rheumatoid arthritis).
6. Serum creatine kinase levels may be slightly elevated.
Electrophysiologic Findings
1. Sensory and motor conduction studies are normal.
2. EMG demonstrates normal-appearing MUAPs that are firing continuously, with coactivation of agnostic and antagonist muscles.
Treatment
1. Symptomatic therapies
a. We usually initiate symptomatic treatment with diazepam 2 mg b.i.d. working up to a dosage of 5 to 20 mg t.i.d. to q.i.d. These patients tolerate, and can benefit from, large doses of diazepam if introduced slowly.
b. Another option is 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. We 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 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 and then 0.75 to 1.5 mg/kg every other day (q.o.d.) for 2 to 4 months is tried if IVIG is ineffective. If prednisone is beneficial, we taper the prednisone to the lowest dose that controls the symptoms. We do not use prednisone in patients with diabetes mellitus.
d. Other immunotherapies (eg, rituximab, azathioprine, mycophenolate mofetil; Table 12-1) may be tried.
Table 12-1 Immunosuppressive and Immunomodulatory Therapies Commonly Used in Neuromuscular Disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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ISAAC SYNDROME/PERIPHERAL NERVE HYPEREXCITABILITY SYNDROMES
Background
1. These disorders are caused by hyperexcitability of the motor nerves, resulting in continuous activation of muscle fibers.
2. They form a spectrum of diseases with considerable clinical and etiological overlap, including cramp-fasciculation syndrome (CFS), Isaac syndrome, and Morvan syndrome.
3. Most patients develop these disorders sporadically; however, several families with apparent autosomal dominant inheritance have been reported. They may also occur in association with other autoimmune disorders (eg, SLE, systemic sclerosis, celiac disease), as well as myasthenia gravis and thymoma
4. Paraneoplastic neuromyotonia has been reported with lung carcinoma, plasmacytoma, and Hodgkin lymphoma.
5. Generalized myokymia or neuromyotonia may complicate hereditary motor and sensory neuropathies (eg, Charcot-Marie-Tooth [CMT] disease), chronic inflammatory demyelinating polyneuropathy (CIDP), and autosomal dominant episodic ataxia.
Pathophysiology
Peripheral nerve hyperexcitability syndromes, in particular Isaacs syndrome and Morvan syndrome, are autoimmune disease caused by autoantibodies directed against voltage-gated potassium channel complex located on peripheral nerves, in particular contactin-associated protein-like 2 and leucine-rich glioma inactivated 1.
Prognosis
Most patients respond well to treatment.
Diagnosis
Clinical Features
1. CFS predominantly presents with muscle stiffness, cramps, and fasciculations, without other neurological findings, and rarely associated with a tumor.
2. Isaac syndrome
a. Usually occurs in adults but has been observed in the newborn.
b. Patients manifest with diffuse muscle stiffness, widespread muscle twitching (myokymia), cramps, increased sweating.
c. The myokymia is present continuously even during sleep.
d. The muscle stiffness worsens with voluntary activity of the affected body segment.
e. Patients may experience difficulty relaxing muscles following maximal contraction (ie, pseudomyotonia).
f. Some patients experience numbness, paresthesias, and weakness.
3. Morvan syndrome has the same features as Isaac syndrome with the addition of encephalopathy (including confusion, hallucinations, insomnia) and prominent dysautonomia.
Laboratory Features
1. Antibodies directed against voltage-gated potassium channel complex are detectable in the serum and CSF. Given its lack of specificity, it is important to follow this by confirming the presence of antibodies against contactin-associated protein-like 2 and leucine-rich glioma inactivated 1.
2. Patients may have other laboratory features associated with concomitant autoimmune diseases, and it is important to exclude the possibility of underlying malignancy.
3. CSF may demonstrate increased protein, increased immunoglobulins, and oligoclonal bands.
Electrophysiologic Findings
1. After-discharges may be 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. Symptomatic treatment with AEDs (eg, phenytoin, carbamazepine, and gabapentin) may also useful as well, perhaps by decreasing neuronal excitability by blocking sodium channels. These may be the only treatment needed for CFS.
2. Various modes of immunomodulation appear to be beneficial in some patients with Isaac syndrome and Morvan syndrome, including plasmapheresis, IVIG, and corticosteroid treatment.
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. Nearly all cases of tetanus occur in people who have never been vaccinated or in adults who have not kept up to date on their booster shots.
Pathophysiology
1. The bacteria or their spores gain access to the patient typically through a minor wound.
2. In the 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 caused by this organism is variable, depending on the sophistication of health care delivery and immunizations.
2. In the United States, the mortality caused by tetanus intoxication is less than 0.1/100,000.
3. The high number of worldwide deaths from neonatal tetanus (787,000 newborn deaths globally in 1988, based on the World Health Organization [WHO]) led to placing its elimination as a goal in the late 1980s. The most recent WHO estimates from 2018 reported 25,000 newborns died from neonatal tetanus, a 97% reduction from the earlier number.
Diagnosis
1. The clinical presentation of tetanus is subdivided into four major categories:
a. Local
b. Cephalic
c. Generalized
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. Some patients develop trismus (difficulty opening the mouth secondary to masseter muscle contraction).
5. Progression would lead 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, opisthotonus, 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. Once the massive whole-body contractions start, there is little doubt as to the diagnosis.
6. Tetanus occurring during pregnancy or within 6 weeks of the end of pregnancy is called maternal tetanus.
7. Neonatal tetanus occurring within the first 28 days of life is called neonatal tetanus and 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.
Treatment
1. Patients should undergo wound debridement to eradicate necrotic tissue and spores.
2. Patients with suspected tetanus intoxication should be hospitalized and evaluated for existent or impending airway compromise.
3. Human tetanus immunoglobulin should be administered (single dose of 500 units intramuscularly, per the CDC) as well as adsorbed tetanus toxoid at a different site.
4. The antibiotic of choice is metronidazole (500 mg IV every 6 hours for 7-10 days).
5. If airway compromise is noted, there is a good chance that this situation will persist for some time and a tracheotomy should be considered.
6. 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.
7. If autonomic symptoms or signs develop, these should be treated immediately with appropriate medications.
8. 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 inflammatory 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. Other rare variants have been reported including acute pandysautonomia (acute autonomic dysfunction, hyporeflexia, and possible sensory symptoms), pure sensory GBS, and facial diplegia with distal limb paresthesia.
4. 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. C. jejuni has been reported to produce antibodies against GM1, GD1a, GalNac-GD1a, and GD1b gangliosides, which are strongly associated with AMAN and AMSAN.
4. Although some reports have suggested association with Zika virus and coronavirus disease 2019 (COVID-19), a direct causal relationship has not been established.
5. Vaccination and GBS
a. A similar immunologic mechanism of molecular mimicry has been suggested for cases that follow immunization.
b. The risk of GBS triggered by acute influenza infection is much higher, and the detrimental health effects of infection much greater, than the minor risk of GBS associated with the vaccine (some studies report no association with current vaccination).
c. Rare cases of GBS have been reported with the quadrivalent meningococcal conjugate vaccine, the recombinant zoster vaccine and the adenovirus vector COVID-19 vaccine, but not with other forms of COVID-19 vaccines.
6. 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 more than 8 weeks, is more consistent with CIDP. 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 may develop in some patients. Weakness of neck flexion and shoulder abduction correlate with diaphragmatic failure to some extent.
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, with 80% being able to walk independently by 1 year. About 15% of patients are without any residual deficits 1 to 2 years after disease onset, and 5% to 10% 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 ventilatory 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 60 years, abrupt onset of profound weakness, the need for mechanical ventilation, preceding diarrheal illness, and distal CMAP amplitudes less than 10% to 20% of the normal.
7. The Erasmus GBS outcome score (EGOS) and modified Erasmus global outcome score (mEGOS) can estimate the risk of being unable to walk at 6 months, using elements of age, history of diarrhea, GBS disability score, and Medical Research Council sum scores at 2 and 1 week, respectively (some limitations as studied for the White Dutch population) (https://gbstools.erasmusmc.nl/prognosis-tool/0/0/6-months).
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 more than 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 HIV infection, CNS lymphoma/leukemia, neurosarcoidosis, and poliomyelitis need to be considered.
3. Elevated liver function tests 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. Anti-GM1 antibodies are associated 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 demyelinating process.
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 may be 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 distal motor nerve terminals and proximal spinal roots in AIDP, respectively.
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 or mildly slowed 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 NCS are similar to those in AMSAN except that sensory conductions are normal.
Treatment
1. Patients showing signs autonomic dysfunction or at risk of respiratory failure, including those with severe or rapidly progressive weakness, need to be admitted to an intensive care unit. The Erasmus GBS Respiratory Insufficiency Score, can be used to predict the risk of respiratory failure within the first week (https://gbstools.erasmusmc.nl/prognosis-tool). It incorporates the time interval from the onset of weakness to hospital admission, presence of bulbar or facial weakness, and MRC sum score. Erasmus GBS Respiratory Insufficiency Score scores suggest the risk of respiratory failure as 0 to 2 (low risk 4%), 3 to 4 (intermediate risk of 24%), and 5 to 7 (high risk of 65%).
2. There have been no treatment trials devoted solely to AMAN or AMSAN. Nevertheless, treatments used for AIDP are given to all patients with GBS-related neuropathies with any substantial disability.
3. Treatment is generally instituted when the patient is no longer able to walk; however, those who are still able to walk but continue to deteriorate because of illness are also treated. Treatment should begin as soon as possible, preferably within the first 7 to 10 days of symptoms.
4. Plasma exchange and IVIG have been demonstrated in prospective controlled trials to be equally effective in the treatment of GBS.
5. The total plasma exchange is 200 to 250 mL/kg of patient body weight spread over 10 to 14 days. The removed plasma is generally replaced with albumin. 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.
6. IVIG has replaced plasma exchange in many centers because it is easier to administer than the latter, at least as effective, and more widely available. The total dose of IVIG is 2.0 g/kg body weight, which is split to be infused over 5 days.
7. There is no added benefit of IVIG following plasma exchange.
8. The mean time to improvement of one clinical grade in the various controlled, randomized, plasma exchange, 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 plasma exchange or IVIG treatments. There is no evidence that plasma exchange beyond 250 mL/kg or IVIG greater than 2 g/kg is of any added benefit. Repeated courses of IVIG are sometimes used in patients who are not improving, but there is limited evidence for this approach.
9. As many as 10% of patients treated with either plasma exchange or IVIG develop a relapse following initial improvement. In patients who suffer such relapses, we give additional courses of PE or IVIG.
10. Respiratory care
a. Monitor FVC and negative inspiratory force (NIF) for signs of respiratory distress. FVC and NIF 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.
11. 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.
12. 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.
c. Monitoring for, and treating, autonomic dysfunction is important, in particular in the first few days of the disease process.
13. Neuropathic pain control is important (see section on Neuropathy Treatment section).
14. The issue of immunizations for patients who have had GBS is not settled. In cases that GBS has 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 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 2:1 male predominance with a mean age of onset in the early 40s.
3. An antecedent infection occurs in more than two-thirds of cases, the most common being Haemophilus influenzae and C. jejuni.
Pathophysiology
1. Thought to be through molecular mimicry, where 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%) and ataxia is evident in 21% at the onset.
2. Ophthalmoparesis can develop asymmetrically but often progresses to complete ophthalmoplegia. 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 more than 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. Whether mild cases require treatment, particularly if walking is preserved, is uncertain.
3. We treat patients with severe disease with either IVIG 2 g/kg over 5 days or PE 250 mL/kg over 2 weeks, similar to GBS.
IDIOPATHIC AUTONOMIC NEUROPATHY AND PURE PANDYSAUTONOMIA
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. Patients may have antibodies directed against calcium channels or acetylcholine receptors located in 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 more than 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. Antiganglionic acetylcholine receptor antibodies are reported to be present in half of the patients with autoimmune autonomic ganglionopathy.
3. Supine plasma norepinephrine levels are normal, but standing levels are significantly reduced, when compared to normal controls.
Autonomic Testing
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