Neuromuscular Complications of General Medical Disorders

Disorders of the Motor Neuron

Amyotrophic lateral sclerosis (ALS) is the most common and prototypic motor neuron disease. It presents with flaccid weakness and atrophy of muscles without associated pain or sensory disturbances. Degeneration of upper motor neurons also occurs, producing spasticity and hyperreflexia in wasted limbs. Most cases are sporadic, but approximately 10 percent are inherited in autosomal-dominant or -recessive patterns. The pathogenesis of ALS is not known, but it is possible that multiple pathogenic mechanisms are at play, including impaired cellular handling of oxidative stress, neuroinflammation, neurotrophic factor deficiency, glutamate-induced excitotoxicity, and defects in protein metabolism and autophagy. There is no cure for ALS, although riluzole and edavarone modestly slow progression of disease. Noninvasive ventilation, careful nutritional monitoring and supplementation, and multidisciplinary care can improve the quality of life. A sporadic clinical variant characterized by solely lower motor neuron involvement (progressive muscular atrophy) is managed similarly.

Hereditary anterior horn cell diseases include spinal muscular atrophy (SMA), Kennedy syndrome, and hexosaminidase A deficiency. Biallelic mutations or deletions in the SMN1 gene cause SMA. The copy number of a nearly identical gene, SMN2 , on the same chromosome as SMN1 determines the disease severity and age of onset. Intravenous SMN1 gene replacement using a viral vector and an intrathecally administered antisense oligonucleotide therapy have been approved for this condition. Kennedy disease (spinal and bulbar muscular atrophy) is an X-linked disease characterized by proximal muscle weakness, muscle atrophy, and fasciculations, especially periorally. Affected individuals often have gynecomastia and testicular atrophy with reduced fertility. Expansion of a CAG repeat in the androgen receptor gene is responsible.

Compression of the spinal cord may result in segmental loss of anterior horn cells. In cervical spondylosis, combined injury to both the anterior horn cells and descending corticospinal tracts may occur, leading to atrophy and weakness in the hands combined with spastic paraparesis; such a presentation mimics that of ALS.

Many viruses have central nervous system (CNS) tropism, but only a few strains cause acute and selective loss of anterior horn cells. Poliovirus is an enterovirus spread via a fecal–hand–oral route. Most patients are either asymptomatic or develop only mild constitutional symptoms. More severe signs and symptoms may occur in nonparalytic poliomyelitis, and the cerebrospinal fluid (CSF) findings are often indicative of aseptic meningitis. Individuals developing acute paralytic poliomyelitis experience constitutional symptoms but also develop rapidly progressive weakness over the course of one to a few days. Weakness is often focal and asymmetric in the limbs or bulbar muscles, but may be symmetric or generalized. It frequently improves over several weeks to months. Rarely, the live-attenuated oral poliovirus vaccine can cause paralytic poliomyelitis. In the United States, an inactivated poliovirus vaccine is used, which does not carry the risk of vaccine-associated poliomyelitis.

Postpolio syndrome consists of slowly progressive new or worsened weakness, together with fatigue or pain in the muscles or joints, typically occurring many years after acute paralytic poliomyelitis in about 20 to 40 percent of individuals. The pathogenesis may involve late denervation of previously reinnervated muscle fibers or musculoskeletal abnormalities.

Viruses other than poliovirus, such as West Nile virus (WNV), echovirus, coxsackievirus, herpes zoster virus, and Epstein–Barr virus may also cause loss of motor neurons. Only about 20 percent of WNV infections are symptomatic, usually manifesting as a febrile illness. A maculopapular rash is common. About 1 percent of infected individuals develop neurologic symptoms that may include meningoencephalitis, flaccid paralysis, or both. As in poliovirus infection, the weakness is often proximal and asymmetric, with no significant sensory abnormalities. The CSF shows a lymphocytic or neutrophilic pleocytosis (30 to 150 cells/mm ³ ) and high protein content. CSF and serum should be screened for IgM antibodies to WNV. Adding WNV polymerase chain reaction (PCR) testing of both the serum and CSF can increase the diagnostic yield. Treatment is supportive. Rarely, WNV may present with brachial plexopathy, rhabdomyolysis, or a predominantly demyelinating polyneuropathy similar to Guillain–Barré syndrome (GBS).

Paraneoplastic lower motor neuron involvement may occur rarely with lymphoproliferative disorders, thymoma, and various cancers (bronchial, ovarian, renal, and prostate). Patients may have anti-Hu (ANNA-1) and anti-Yo (PCA-1) antibodies, CSF protein level is often elevated, and there is a variable CSF pleocytosis. The weakness may improve after treatment of the cancer.

Radiculopathy

Pain or numbness in a dermatomal pattern accompanied by weakness in a segmental pattern suggests a radiculopathy. External compression is the most frequent cause of nerve root injury, by either intervertebral disc herniation or spondylosis. Radiculopathy resulting from degenerative spine disease is discussed further in Chapter 22 . Other causes of radiculopathy may include gouty spine disease, Paget disease, Tarlov cysts, and methylacrylate extrusion during spine surgery. Extradural tumors such as schwannomas, neurofibromas, and meningiomas may also produce a radiculopathy. A radiculopathy sometimes results from epidural or spinal anesthesia; the injury may result from direct trauma to the nerve or from chemical injury related to the injected substance.

Diabetic thoracoabdominal radiculopathy (diabetic truncal neuropathy) is a common cause of noncompressive radiculopathy. Patients present with pain and hyperalgesia in a region along the chest or abdomen. The pattern of involvement may be clearly dermatomal, but often the changes span more than one segment. Segmental weakness may manifest as an outpouching of the abdominal wall. The pathophysiology is unclear, but an inflammatory vasculopathy may be responsible.

Compression of multiple lumbosacral nerve roots produces a cauda equina syndrome, which may lead to permanent urinary and fecal incontinence and lower extremity weakness and numbness and thus constitutes a neurosurgical emergency. The usual cause is a large, midline disc herniation. Chronic cauda equina syndrome may be caused by a developmental anomaly, such as a tethered spinal cord.

Spondylosis is the most common cause of polyradiculopathy, although metastatic spinal disease should also be considered. Cancers of the breast, lung, prostate, or kidney, or multiple myeloma metastasize most frequently to the spine. Polyradiculopathy results from direct tumor compression or from leptomeningeal infiltration of the roots by tumor cells (neoplastic meningitis). Treatment of spinal bony metastases often involves external beam irradiation, although decompressive surgery may be necessary in radiation-resistant tumors.

Carcinomatous meningitis often affects the caudal roots first. Cranial neuropathies, meningeal signs and symptoms, and a myelopathy may be associated features. CSF analysis typically shows a pleocystosis, hypoglycorrhachia, elevated protein level, and malignant cells on cytologic analysis. The yield of positive cytology for malignant cells is increased significantly by repeating the lumbar puncture. Treatment is usually palliative and includes radiation therapy and intrathecal chemotherapy. The median survival of patients with leptomeningeal metastases is 4 months.

Infectious causes of polyradiculopathy include cytomegalovirus (CMV), Borrelia burgdorferi (Lyme disease), Epstein–Barr virus, herpes simplex virus, Mycobacterium tuberculosis , and Treponema pallidum . CMV polyradiculopathy usually presents as a late complication of acquired immunodeficiency syndrome (AIDS), but it can be a presenting manifestation of human immunodeficiency virus (HIV) infection. The onset of flaccid paraparesis, lower extremity numbness, and urinary retention may be acute or subacute. A neutrophilic pleocytosis on CSF analysis is a clue to the diagnosis; the diagnosis is confirmed by a culture or CMV DNA PCR assay on CSF. Treatment includes ganciclovir, foscarnet, or both.

Arachnoiditis is a nonspecific term for inflammation of the spinal leptomeninges. Historically, arachnoiditis has been associated with tuberculous and syphilitic meningitis and with obsolete oil-based contrast agents for myelography. Currently, the term often refers to the appearance of thickened meninges and clumping of the nerve roots on magnetic resonance imaging (MRI) of the spine, usually in patients who have undergone lumbar spine surgery. There is controversy about the association of the imaging findings, clinical findings, and symptoms. Arachnoiditis has also been described in association with toxoplasmosis and subarachnoid hemorrhage; sometimes the cause is not known.

Disorders of Posterior Root Ganglia

Diffuse or regional impairment of tactile sensation or gait ataxia without weakness suggests degeneration of posterior root ganglia cells (sensory neuronopathy). Patients may also have facial numbness and autonomic involvement, manifesting as gastroparesis, orthostatic hypotension, sexual impairment, and Adie pupils. EMG and NCSs differentiate sensory neuronopathies from more common distal sensory axonal polyneuropathies. Sensory neuronopathies may be acquired ( Table 60-2 ) or hereditary.

Paraneoplastic sensory neuronopathy (see Chapter 27 ) is commonly associated with small cell lung cancer but also occurs with breast or ovarian cancer, Hodgkin lymphoma, neuroendocrine tumors, and sarcoma. Symptom onset is generally subacute. Antibodies to the Hu antigen (ANNA-1) are usually present, but their absence does not exclude the possibility of paraneoplastic sensory neuronopathy. Antibodies to the collapsin response-mediator protein 5 (CRMP5) have also been described in some patients with small cell lung cancer. Sensory neuronopathy may occur with other paraneoplastic syndromes. Management is directed to the diagnosis and treatment of the underlying cancer. Treatment of the paraneoplastic condition with intravenous immunoglobulin (IVIg), plasmapheresis, or other immunosuppressive therapies is often disappointing.

Autoimmune or inflammatory conditions associated with sensory neuronopathy (sometimes as the initial manifestation) include Sjögren’s syndrome and autoimmune hepatitis. The posterior root ganglia of patients are infiltrated by T lymphocytes. IVIg and plasmapheresis have benefited some patients.

An acute sensory neuronopathy syndrome characterized by the acute onset of widespread sensory symptoms, areflexia, impaired vibratory sensation, and gait ataxia has developed 4 to 12 days after initial antibiotic treatment for a febrile illness. The underlying pathogenesis in such cases may be infectious, postinfectious, or toxic (related to antibiotic use).

Infectious causes of sensory neuronopathy are shown in Table 60-2 . HIV infection may cause a sensory neuronopathy. T-cell infiltration of dorsal root ganglia has been found in patients with end-stage AIDS. Many of these patients also have pallor of the cervical portion of the gracile tract at autopsy, suggesting that a “dying-back” axonopathy occurs along with sensory neuron loss.

Latent infection of the dorsal root ganglia occurs following primary varicella zoster virus infection. When cell-mediated immunity is compromised, reactivation of viral replication causes the clinical syndrome of herpes zoster. The elderly, transplant recipients, and HIV-positive patients are particularly vulnerable. The prodromal stage of herpes zoster includes fevers, dysesthesias, and malaise. Several days later, a vesicular eruption appears in a dermatomal distribution. Pathologically, there is intense inflammation of the dorsal root ganglia. Once the lesions become encrusted, they are no longer infectious. Approximately 3 percent of patients develop segmental paresis, perhaps from spread of the virus to the anterior horn cells. Most patients recover muscle strength with time. Treatment during the early stages of infection includes acyclovir, valacyclovir, or famcyclovir. Postherpetic neuralgia may occur, particularly in the elderly. Tricyclic drugs or anticonvulsants are effective treatments, as discussed in Chapter 42 . Patients age 50 and older with a history of herpes zoster and immunocompetent patients age 60 or older without a history of herpes zoster should receive the zoster vaccine.

A number of toxins and vitamin deficiencies cause sensory neuronopathy. Because many of these also cause an axonopathy, they are discussed later (pp. 1071–1073).

Hereditary sensory neuronopathy (hereditary sensory and autonomic neuropathy) is both genetically and phenotypically heterogeneous; some forms present with predominantly small-fiber involvement, whereas others have mixed small- and large-fiber involvement. There is variable involvement of the autonomic nervous system. Commercial genetic testing is available for some types.

Plexopathy

Trauma and compression, including at childbirth, cause most plexus injuries; other causes include tumor infiltration, postirradiation injury, and infection. An autoimmune monophasic neuritis, often idiopathic but sometimes associated with diabetes mellitus, may involve portions of either the brachial or lumbosacral plexus.

Sports, motorcycle, and industrial accidents cause traction injury to the brachial plexus. If the arm is located at the side of the patient at the time of impact or is distracted away from the torso, the upper roots and plexus are preferentially injured. If the arm is elevated above the head, the lower trunks and roots are most vulnerable. Compression injury of the brachial or lumbosacral plexus may occur during surgery or coma or from mass lesions such as a hematoma or tumor.

Immune brachial plexopathy (brachial plexus neuritis, neuralgic amyotrophy, Parsonage–Turner syndrome) is an acute monophasic neuropathy that presents with severe shoulder pain accompanied by muscle weakness and atrophy. Both sporadic and hereditary forms exist. Proximal muscle groups are more commonly affected than distal ones; involvement may be either unilateral or bilateral. Sensory loss is mild. Ipsilateral diaphragmatic weakness sometimes occurs from phrenic nerve involvement. Nerve biopsy specimens have revealed perineurial thickening and perivascular inflammatory infiltrates. Corticosteroids or IVIg, or both, have been used in treatment with anecdotally reported success, but controlled studies are needed. Aggressive treatment to control pain is important. The prognosis is excellent, with 60 percent of patients recovering completely within 1 year and 80 percent within a few years.

Nondiabetic lumbosacral radiculoplexus neuropathy refers to a similar disorder that affects the lower extremities. As with immune brachial plexus neuropathy, pain is often the initial symptom. It may occur in the back, buttock, thigh, or leg. Proximal weakness is more common than distal weakness. In time, however, the weakness often becomes more diffuse in the limb, and bilateral involvement is common. Clinically, sensory deficits (despite the pain) tend to be relatively mild. Nerve biopsies have shown evidence of ischemic injury and epineurial perivascular inflammatory collections. Some improvement in strength occurs with time but long-standing motor deficits are common. Case reports suggest a potential benefit of corticosteroids, plasmapheresis, or IVIg therapy, but no positive controlled trials have been published. Diabetic lumbosacral radiculoplexopathy (proximal diabetic neuropathy; diabetic amyotrophy) is discussed in Chapter 19 .

Breast and lung cancers are the two most common secondary neoplasms to infiltrate the brachial plexus. Gastrointestinal and genitourinary cancers, melanomas, and lymphomas may also metastasize to the brachial plexus. Colorectal cancer is the most common neoplasm to infiltrate the lumbosacral plexus, but uterine, prostate, and ovarian cancer may also do so; other neoplasms may spread to the lumbosacral plexus metastatically.

Radiation therapy that includes the plexus in the field (as for breast cancer) may produce delayed weakness, dysesthesias, and numbness in the affected limb ( Chapter 28 ). Irradiation causes marked fibrosis of the nerve fibers, loss of myelin, and destruction of the vascular supply. The period between the radiation treatment and onset of symptoms ranges from a few weeks to more than 30 years. Paresthesias in the median-innervated digits are a common initial symptom. Subsequently, weakness of the intrinsic hand muscles develops. Prominent limb pain and a Horner syndrome suggest tumor involvement rather than radiation-induced injury, whereas the presence of fasciculation potentials and myokymia on needle EMG suggests radiation injury. Distinction of these two disorders is aided by MRI.

Patients with radiation-induced lumbosacral plexopathy have generally been treated for lymphoreticular, testicular, uterine, or ovarian cancer. Patients usually present with slowly progressive distal weakness; numbness or paresthesia is less common. Mild pain occurs in 50 percent of patients. The CSF protein concentration may be elevated. As with radiation-induced brachial plexopathy, the condition may stabilize, but patients are often disabled.

Finally, a lower motor neuron syndrome affecting the legs, with relatively intact sensation, may also occur following irradiation of the distal spinal cord and cauda equina. Patients have generally received more than 40 Gy. Pathologic examination of the cauda equina shows a vasculopathy of the proximal nerve roots. Although the condition eventually stabilizes, patients are usually left with significant disabilities. There is no treatment.

Neurogenic thoracic outlet syndrome occurs when an anomalous fibrous band between the first thoracic rib and a cervical rib or elongated transverse process on the seventh vertebral body exerts pressure on the first thoracic nerve root or the lower trunk of the brachial plexus. This leads to wasting and atrophy of the hand muscles, particularly of the thenar eminence, and intermittent pain and paresthesias of the inner arm and medial hand, including the fourth and fifth digits. Electrodiagnostic studies confirm the diagnosis. A chest x-ray may show the cervical rib or an elongated transverse process ( Fig. 60-1 ); the fibrous band shows up as a radiolucency. MRI may be helpful in showing and localizing plexus involvement ( Fig. 60-2 ). Treatment is surgical.

Peripheral Neuropathy

The distribution of findings may suggest either a focal, multifocal, or generalized/symmetric pattern of nerve involvement. For the multifocal and generalized neuropathies in particular, identifying the relative involvement of motor and sensory fibers ( Tables 60-3 to 60-5 ) narrows the differential diagnosis. Sensory neuropathies may be further subdivided according to whether predominantly large- or small-diameter fibers are affected ( Tables 60-4 and 60-5 ). Knowing whether the pathogenesis is predominantly axonal or demyelinating ( Tables 60-6 and 60-7 ) also refines the diagnostic search. Generally, patients with axonal neuropathies present with predominantly sensory signs and symptoms, whereas patients with demyelinating neuropathies have more significant weakness. Given the exceptions to this rule, however, NCSs must be performed to distinguish between these two possibilities. Finally, the time course of symptom onset has important implications for pathogenesis ( Table 60-8 ). Discussion here focuses on those peripheral neuropathies associated with systemic diseases.