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InternalMed_Harrison. CMV can cause an acute lumbosacral polyradiculopathy and multiple mononeuropathies in patients with HIV infection and in other immune deficiency conditions (Chap. 219). EBV infection has been associated with GBS, cranial neuropathies, mononeuropathy multiplex, brachial plexopathy, lumbosacral radiculoplexopathy, and sensory neuronopathies (Chap. 218). Hepatitis B and C can cause multiple mononeuropathies related to vasculitis, AIDP, or CIDP (Chap. 362). Patients with malignancy can develop neuropathies due to (1) a direct effect of the cancer by invasion or compression of the nerves, (2) remote or paraneoplastic effect, (3) a toxic effect of treatment, or (4) as a consequence of immune compromise caused by immunosuppressive medications. The most common associated malignancy is lung cancer, but neuropathies also complicate carcinoma of the breast, ovaries, stomach, colon, rectum, and other organs, including the lymphoproliferative system.


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InternalMed_Harrison. Paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/SN) usually complicates small-cell lung carcinoma (Chap. 122). Patients usually present with numbness and paresthesias in the distal extremities that are often asymmetric. The onset can be acute or insidiously progressive. Prominent loss of proprioception leads to sensory ataxia. Weakness can be present, usually secondary to an associated myelitis, motor neuronopathy, or concurrent Lambert-Eaton myasthenic syndrome (LEMS). Many patients also develop confusion, memory loss, depression, hallucinations or seizures, or cerebellar ataxia. Polyclonal antineuronal antibodies (IgG) directed against a 35to 40-kDa protein or complex of proteins, the so-called Hu antigen, are found in the sera or CSF in the majority of patients with paraneoplastic PEM/SN. CSF may be normal or may demonstrate mild lymphocytic pleocytosis and elevated protein. PEM/SN is probably the result of antigenic similarity between proteins expressed in the tumor


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InternalMed_Harrison. PEM/SN. CSF may be normal or may demonstrate mild lymphocytic pleocytosis and elevated protein. PEM/SN is probably the result of antigenic similarity between proteins expressed in the tumor cells and neuronal cells, leading to an immune response directed against both cell types. Treatment of the underlying cancer generally does not affect the course of PEM/ SN. However, occasional patients may improve following treatment of the tumor. Unfortunately, plasmapheresis, intravenous immunoglobulin, and immunosuppressive agents have not shown benefit.


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InternalMed_Harrison. Malignant cells, in particular leukemia and lymphoma, can infiltrate cranial and peripheral nerves, leading to mononeuropathy, mononeuropathy multiplex, polyradiculopathy, plexopathy, or even a generalized symmetric distal or proximal and distal polyneuropathy. Neuropathy related to tumor infiltration is often painful; it can be the presenting manifestation of the cancer or the heralding symptom of a relapse. The neuropathy may improve with treatment of the underlying leukemia or lymphoma or with glucocorticoids.


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InternalMed_Harrison. Neuropathies may develop in patients who undergo bone marrow transplantation (BMT) because of the toxic effects of chemotherapy, radiation, infection, or an autoimmune response directed against the peripheral nerves. Peripheral neuropathy in BMT is often associated with graft-versus-host disease (GVHD). Chronic GVHD shares many features with a variety of autoimmune disorders, and it is possible that an immune-mediated response directed against peripheral nerves is responsible. Patients with chronic GVHD may develop cranial neuropathies, sensorimotor polyneuropathies, multiple mononeuropathies, and severe generalized peripheral neuropathies resembling AIDP or CIDP. The neuropathy may improve by increasing the intensity of immunosuppressive or immunomodulating therapy and resolution of the GVHD.


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InternalMed_Harrison. Lymphomas may cause neuropathy by infiltration or direct compression of nerves or by a paraneoplastic process. The neuropathy can be purely sensory or motor, but most commonly is sensorimotor. The pattern of involvement may be symmetric, asymmetric, or multifocal, and the course may be acute, gradually progressive, or relapsing and remitting. EDx can be compatible with either an axonal or demyelinating process. CSF may reveal lymphocytic pleocytosis and an elevated protein. Nerve biopsy may demonstrate endoneurial inflammatory cells in both the infiltrative and the paraneoplastic etiologies. A monoclonal population of cells favors lymphomatous invasion. The neuropathy may respond to treatment of the underlying lymphoma or immunomodulating therapies.


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InternalMed_Harrison. Multiple myeloma (MM) usually presents in the fifth to seventh decade of life with fatigue, bone pain, anemia, and hypercalcemia (Chap. 136). Clinical and EDx features of neuropathy occur in as many as 40% of patients. The most common pattern is that of a distal, axonal, sensory, or sensorimotor polyneuropathy. Less frequently, a chronic demyelinating polyradiculoneuropathy may develop (see POEMS, Chap. 460). MM can be complicated by amyloid polyneuropathy and should be considered in patients with painful paresthesias, loss of pinprick and 2686 temperature discrimination, and autonomic dysfunction (suggestive of a small-fiber neuropathy) and CTS. Expanding plasmacytomas can compress cranial nerves and spinal roots as well. A monoclonal protein, usually composed of γ or μ heavy chains or κ light chains, may be identified in the serum or urine. EDx usually shows reduced amplitudes with normal or only mildly abnormal distal latencies and conduction velocities. A superimposed median


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InternalMed_Harrison. or κ light chains, may be identified in the serum or urine. EDx usually shows reduced amplitudes with normal or only mildly abnormal distal latencies and conduction velocities. A superimposed median neuropathy at the wrist is common. Abdominal fat pad, rectal, or sural nerve biopsy can be performed to look for amyloid deposition. Unfortunately, the treatment of the underlying MM does not usually affect the course of the neuropathy.


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InternalMed_Harrison. NEUROPATHIES ASSOCIATED WITH MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (SEE CHAP. 460) Toxic Neuropathies Secondary to Chemotherapy Many of the commonly used chemotherapy agents can cause a toxic neuropathy (Table 459-7). The mechanisms by which these agents cause toxic neuropathies vary, as does the specific type of neuropathy produced. The risk of developing a toxic neuropathy or more severe neuropathy appears to be greater in patients with a preexisting neuropathy (e.g., Charcot-Marie-Tooth disease, diabetic neuropathy) and those who also take other potentially neurotoxic drugs (e.g., nitrofurantoin, isoniazid, disulfiram, pyridoxine). Chemotherapeutic agents usually cause a sensory greater than motor length-dependent axonal neuropathy or neuronopathy/ganglionopathy. Neuropathies can develop as complications of toxic effects of various drugs and other environmental exposures (Table 459-8). The more common neuropathies associated with these agents are discussed here.


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InternalMed_Harrison. Chloroquine and hydroxychloroquine can cause a toxic myopathy characterized by slowly progressive, painless, proximal weakness and atrophy, which is worse in the legs than the arms. In addition, neuropathy can also develop with or without the myopathy leading to sensory loss and distal weakness. The “neuromyopathy” usually appears in patients taking 500 mg daily for a year or more but has been reported with doses as low as 200 mg/d. Serum CK levels are usually elevated due to the superimposed myopathy. NCS reveal mild slowing of motor and sensory NCVs with a mild to moderate reduction in the amplitudes, although NCS may be normal in patients with only the myopathy. EMG demonstrates myopathic muscle action potentials (MUAPs), increased insertional activity in the form of positive sharp waves, fibrillation potentials, and occasionally myotonic potentials, particularly in the proximal muscles. Neurogenic MUAPs and reduced recruitment are found in more distal muscles. Nerve biopsy


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InternalMed_Harrison. waves, fibrillation potentials, and occasionally myotonic potentials, particularly in the proximal muscles. Neurogenic MUAPs and reduced recruitment are found in more distal muscles. Nerve biopsy demonstrates autophagic vacuoles within Schwann cells. Vacuoles may also be evident in muscle biopsies. The pathogenic basis of the neuropathy is not known but may be related to the amphiphilic properties of the drug. These agents contain both hydrophobic and hydrophilic regions


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InternalMed_Harrison. Drug Mechanism of Neurotoxicity Clinical Features Nerve Histopathology EMG/NCS Vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine) Taxanes (paclitaxel, docetaxel) Bortezomib (Velcade) Interfere with axonal microtubule assembly; impairs axonal transport Preferential damage to dorsal root ganglia: ? binds to and cross-links DNA ? inhibits protein synthesis ? impairs axonal transport Promotes axonal microtubule assembly; interferes with axonal transport Unknown; ? inhibition of neurotrophic growth factor binding; ? neuronal lysosomal storage Unknown; ? immunomodulating effects Unknown; ? selective Schwann cell toxicity; ? immunomodulating effects Unknown; ? selective dorsal root ganglia toxicity Unknown Symmetric, S-M, large-/ small-fiber PN; autonomic symptoms common; infrequent cranial neuropathies Symmetric, predominantly sensory PN; large-fiber modalities affected more than small-fiber Symmetric, length-dependent, sensory-predominant PN


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InternalMed_Harrison. Symmetric, predominantly sensory PN; large-fiber modalities affected more than small-fiber Symmetric, length-dependent, sensory-predominant PN Subacute, S-M PN with diffuse proximal and distal weakness; areflexia; increased CSF protein Length-dependent, sensory-predominant PN; autonomic neuropathy Length-dependent, sensory, predominantly small-fiber PN Axonal degeneration of myelinated and unmyelinated fibers; regenerating clusters, minimal segmental demyelination Loss of large > small myelinated and unmyelinated fibers; axonal degeneration with small clusters of regenerating fibers; secondary segmental demyelination Loss of large > small myelinated and unmyelinated fibers; axonal degeneration with small clusters of regenerating fibers; secondary segmental demyelination Loss of large and small myelinated fibers with primary demyelination and secondary axonal degeneration; occasional epiand endoneurial inflammatory cell infiltrates


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InternalMed_Harrison. Loss of large and small myelinated fibers with primary demyelination and secondary axonal degeneration; occasional epiand endoneurial inflammatory cell infiltrates Loss of myelinated nerve fibers; axonal degeneration; segmental demyelination; no inflammation Axonal sensorimotor PN; distal denervation on EMG; abnormal QST, particularly vibratory perception Low-amplitude or unobtainable SNAPs with normal CMAPs and EMG; abnormal QST, particularly vibratory perception Axonal sensorimotor PN; distal denervation on EMG; abnormal QST, particularly vibratory perception Abnormalities consistent with an axonal S-M PN Features suggestive of an acquired demyelinating sensorimotor PN (e.g., slow CVs, prolonged distal latencies and F-wave latencies, conduction block, temporal dispersion) Axonal, demyelinating, or mixed S-M PN; denervation on EMG Abnormalities consistent with an axonal S-M PN


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InternalMed_Harrison. Axonal, demyelinating, or mixed S-M PN; denervation on EMG Abnormalities consistent with an axonal S-M PN Abnormalities consistent with an axonal sensory neuropathy with early small-fiber involvement (abnormal autonomic studies) Abbreviations: CMAP, compound motor action potential; CSF, cerebrospinal fluid; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barré syndrome; NCS, nerve conduction studies; PN, polyneuropathy; QST, quantitative sensory testing; S-M, sensorimotor; SNAP, sensory nerve action potential. Source: From AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008. Drug Mechanism of Neurotoxicity Clinical Features Nerve Histopathology EMG/NCS


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InternalMed_Harrison. Source: From AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008. Drug Mechanism of Neurotoxicity Clinical Features Nerve Histopathology EMG/NCS Misonidazole Unknown Painful paresthesias and loss of Axonal degeneration of large Low-amplitude or unobtainable largeand small-fiber sensory myelinated fibers; axonal SNAPs with normal or only slightly modalities and sometimes distal swellings; segmental demy-reduced CMAPs amplitudes weakness in length-dependent elination pattern Metronidazole Unknown Painful paresthesias and loss of Axonal degeneration Low-amplitude or unobtainable largeand small-fiber sensory SNAPs with normal CMAPs


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InternalMed_Harrison. Metronidazole Unknown Painful paresthesias and loss of Axonal degeneration Low-amplitude or unobtainable largeand small-fiber sensory SNAPs with normal CMAPs Chloroquine and Amphiphilic properties may Loss of largeand small-fiber sen-Axonal degeneration with Low-amplitude or unobtainable hydroxychloroquine lead to drug-lipid complexes sory modalities and distal weak-autophagic vacuoles in nerves SNAPs with normal or reduced that are indigestible and result ness in length-dependent pattern; as well as muscle fibers CMAP amplitudes; distal denervain accumulation of autopha-superimposed myopathy may tion on EMG; irritability and myogic vacuoles lead to proximal weakness pathic-appearing MUAPs proximally in patients with superimposed toxic myopathy


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InternalMed_Harrison. Amiodarone Amphiphilic properties may Paresthesias and pain with loss Axonal degeneration and Low-amplitude or unobtainable lead to drug-lipid complexes of largeand small-fiber sensory segmental demyelination with SNAPs with normal or reduced that are indigestible and result modalities and distal weakness in myeloid inclusions in nerves CMAP amplitudes; can also have in accumulation of autopha-length-dependent pattern; super-and muscle fibers prominent slowing of CVs; distal gic vacuoles imposed myopathy may lead to and myopathic-appearing MUAPs proximally in patients with superimposed toxic myopathy


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InternalMed_Harrison. Colchicine Inhibits polymerization of Numbness and paresthesias with Nerve biopsy demonstrates Low-amplitude or unobtainable tubulin in microtubules and loss of large-fiber modalities in a axonal degeneration; muscle SNAPs with normal or reduced impairs axoplasmic flow length-dependent fashion; super-biopsy reveals fibers with CMAP amplitudes; irritability and imposed myopathy may lead vacuoles myopathic-appearing MUAPs to proximal in addition to distal proximally in patients with super-weakness Podophyllin Binds to microtubules and Sensory loss, tingling, muscle Axonal degeneration Low-amplitude or unobtainable impairs axoplasmic flow weakness, and diminished SNAPs with normal or reduced muscle stretch reflexes in length- Thalidomide Unknown Numbness, tingling, and burning Axonal degeneration; autopsy Low-amplitude or unobtainable pain and weakness in a length-studies reveal degeneration of SNAPs with normal or reduced dependent pattern dorsal root ganglia CMAP amplitudes


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InternalMed_Harrison. Disulfiram Accumulation of neurofila-Numbness, tingling, and burn-Axonal degeneration with Low-amplitude or unobtainable ments and impaired axoplas-ing pain in a length-dependent accumulation of neurofila-SNAPs with normal or reduced mic flow pattern ments in the axons CMAP amplitudes Dapsone Unknown Distal weakness that may progress Axonal degeneration and seg-Low-amplitude or unobtainable to proximal muscles; sensory loss mental demyelination CMAPs with normal or reduced SNAP amplitudes SNAPs with normal or reduced CMAP amplitudes Nitrofurantoin Unknown Numbness, painful paresthesias, Axonal degeneration; autopsy Low-amplitude or unobtainable and severe weakness that may studies reveal degeneration SNAPs with normal or reduced resemble GBS of dorsal root ganglia and CMAP amplitudes anterior horn cells Pyridoxine Unknown Dysesthesias and sensory ataxia; Marked loss of sensory axons Reduced amplitudes or absent (vitamin B6)


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InternalMed_Harrison. Pyridoxine Unknown Dysesthesias and sensory ataxia; Marked loss of sensory axons Reduced amplitudes or absent (vitamin B6) Isoniazid Inhibits pyridoxal phospho-Dysesthesias and sensory ataxia; Marked loss of sensory axons Reduced amplitudes or absent kinase leading to pyridoxine impaired large-fiber sensory and cell bodies in dorsal root SNAPs and, to a lesser extent, deficiency modalities on examination ganglia and degeneration of CMAPs the dorsal columns Ethambutol Unknown Numbness with loss of large-fiber Axonal degeneration Reduced amplitudes or absent modalities on examination SNAPs Phenytoin Unknown Numbness with loss of large-fiber Axonal degeneration and Low-amplitude or unobtainable modalities on examination segmental demyelination SNAPs with normal or reduced CMAP amplitudes Lithium Unknown Numbness with loss of large-fiber Axonal degeneration Low-amplitude or unobtainable modalities on examination SNAPs with normal or reduced CMAP amplitudes


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InternalMed_Harrison. Lithium Unknown Numbness with loss of large-fiber Axonal degeneration Low-amplitude or unobtainable modalities on examination SNAPs with normal or reduced CMAP amplitudes Drug Mechanism of Neurotoxicity Clinical Features Nerve Histopathology EMG/NCS Unknown; may act as alkylating agent and bind DNA Unknown; may lead to covalent cross-linking between neurofilaments Unknown; may interfere with mitochondria Unknown; may combine with sulfhydryl groups Unknown; may combine with sulfhydryl groups Numbness with loss of large-fiber modalities on examination; sensory ataxia; mild distal weakness Length-dependent numbness and tingling with mild distal weakness Early features are those of neuromuscular blockade with generalized weakness; later axonal sensorimotor PN ensues Acute, severe sensorimotor PN that may resemble GBS Encephalopathy; motor neuropathy (often resembles radial neuropathy with wrist and finger drop); autonomic neuropathy; bluish-black discoloration of gums


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InternalMed_Harrison. Encephalopathy; motor neuropathy (often resembles radial neuropathy with wrist and finger drop); autonomic neuropathy; bluish-black discoloration of gums Encephalopathy; painful sensory symptoms; mild loss of vibration; distal or generalized weakness may also develop; autonomic neuropathy; alopecia Abdominal discomfort, burning pain, and paresthesias; generalized weakness; autonomic insufficiency; can resemble GBS Distal paresthesias and reduction of all sensory modalities Degeneration of sensory axons in peripheral nerves and posterior columns, spinocerebellar tracts, mammillary bodies, optic tracts, and corticospinal tracts in the CNS Axonal swellings with accumulation of neurofilaments Axonal degeneration along with degeneration of gracile fasciculus and corticospinal tracts Axonal degeneration and giant axons swollen with neurofilaments Axonal degeneration of motor axons Axonal degeneration; degeneration of dorsal root ganglia, calcarine, and cerebellar cortex


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InternalMed_Harrison. Axonal degeneration and giant axons swollen with neurofilaments Axonal degeneration of motor axons Axonal degeneration; degeneration of dorsal root ganglia, calcarine, and cerebellar cortex Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Early: repetitive firing of CMAPs and decrement with repetitive nerve stimulation; late: axonal sensorimotor PN Features of a mixed axonal and/or demyelinating sensorimotor axonal PN—reduced amplitudes, prolonged distal latencies, conduction block, and slowing of CVs Reduction of CMAP amplitudes with active denervation on EMG Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes


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InternalMed_Harrison. Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; may have demyelinating features: prolonged distal latencies and slowing of CVs Abbreviations: CMAP, compound motor action potential; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barré syndrome; MUAP, muscle action potential; NCS, nerve conduction studies; PN, polyneuropathy; S-M, sensorimotor; SNAP, sensory nerve action potential Source: From AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008.


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InternalMed_Harrison. that allow them to interact with the anionic phospholipids of cell axonal degeneration. Colchicine inhibits the polymerization of tubulin membranes and organelles. The drug-lipid complexes may be resis-into microtubules. The disruption of the microtubules probably leads to tant to digestion by lysosomal enzymes, leading to the formation of defective intracellular movement of important proteins, nutrients, and autophagic vacuoles filled with myeloid debris that may in turn cause waste products in muscle and nerves. degeneration of nerves and muscle fibers. The signs and symptoms of the neuropathy and myopathy are usually reversible following discon-THALIDOMIDE tinuation of medication. Thalidomide is an immunomodulating agent used to treat mul tiple myeloma, GVHD, leprosy, and other autoimmune disorders. AMIODARONE Thalidomide is associated with severe teratogenic effects as well as Amiodarone can cause a neuromyopathy similar to chloroquine peripheral neuropathy that can be


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InternalMed_Harrison. autoimmune disorders. AMIODARONE Thalidomide is associated with severe teratogenic effects as well as Amiodarone can cause a neuromyopathy similar to chloroquine peripheral neuropathy that can be dose-limiting. Patients develop and hydroxychloroquine. The neuromyopathy typically appears numbness, painful tingling, and burning discomfort in the feet and after patients have taken the medication for 2–3 years. Nerve biopsy hands and less commonly muscle weakness and atrophy. Even after demonstrates a combination of segmental demyelination and axonal stopping the drug for 4–6 years, as many as 50% patients continue loss. Electron microscopy reveals lamellar or dense inclusions in to have significant symptoms. NCS demonstrate reduced amplitudes Schwann cells, pericytes, and endothelial cells. The inclusions in or complete absence of SNAPs, with preserved conduction velocities muscle and nerve biopsies have persisted as long as 2 years following when obtainable. Motor NCS are usually


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InternalMed_Harrison. The inclusions in or complete absence of SNAPs, with preserved conduction velocities muscle and nerve biopsies have persisted as long as 2 years following when obtainable. Motor NCS are usually normal. Nerve biopsy reveals discontinuation of the medication. a loss of large-diameter myelinated fibers and axonal degeneration.


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InternalMed_Harrison. Degeneration of dorsal root ganglion cells has been reported at autopsy. COLCHICINE Colchicine can also cause a neuromyopathy. Patients usually present PYRIDOXINE (VITAMIN B6) TOXICITY with proximal weakness and numbness and tingling in the distal extrem-Pyridoxine is an essential vitamin that serves as a coenzyme for transities. EDx reveals features of an axonal polyneuropathy. Muscle biopsy amination and decarboxylation. However, at high doses (116 mg/d), reveals a vacuolar myopathy, whereas sensory nerves demonstrate patients can develop a severe sensory neuropathy with dysesthesias and sensory ataxia. NCS reveal absent or markedly reduced SNAP amplitudes with relatively preserved CMAPs. Nerve biopsy reveals axonal loss of fiber at all diameters. Loss of dorsal root ganglion cells with subsequent degeneration of both the peripheral and central sensory tracts have been reported in animal models.


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InternalMed_Harrison. One of the most common side effects of isoniazid (INH) is peripheral neuropathy. Standard doses of INH (3–5 mg/kg per day) are associated with a 2% incidence of neuropathy, whereas neuropathy develops in at least 17% of patients taking in excess of 6 mg/kg per day. The elderly, malnourished, and “slow acetylators” are at increased risk for developing the neuropathy. INH inhibits pyridoxal phosphokinase, resulting in pyridoxine deficiency and the neuropathy. Prophylactic administration of pyridoxine 100 mg/d can prevent the neuropathy from developing.


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InternalMed_Harrison. The nucleoside analogues zalcitabine (dideoxycytidine or ddC), didanosine (dideoxyinosine or ddI), stavudine (d4T), lamivudine (3TC), and antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) are used to treat HIV infection. One of the major dose-limiting side effects of these medications is a predominantly sensory, length-dependent, symmetrically painful neuropathy. Zalcitabine (ddC) is the most extensively studied of the nucleoside analogues, and at doses greater than 0.18 mg/kg per day, it is associated with a subacute onset of severe burning and lancinating pains in the feet and hands. NCS reveal decreased amplitudes of the SNAPs with normal motor studies. The nucleoside analogues inhibit mitochondrial DNA polymerase, which is the suspected pathogenic basis for the neuropathy. Because of a “coasting effect,” patients can continue to worsen even 2–3 weeks after stopping the medication. Following dose reduction, improvement in the neuropathy is seen in most patients after


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InternalMed_Harrison. Because of a “coasting effect,” patients can continue to worsen even 2–3 weeks after stopping the medication. Following dose reduction, improvement in the neuropathy is seen in most patients after several months (mean time about 10 weeks).


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InternalMed_Harrison. HEXACARBONS (n-HEXANE, METHYL n-BUTYL KETONE)/GLUE SNIFFER’S NEUROPATHY n-Hexane and methyl n-butyl ketone are water-insoluble industrial organic solvents that are also present in some glues. Exposure through inhalation, accidentally or intentionally (glue sniffing), or through skin absorption can lead to a profound subacute sensory and motor polyneuropathy. NCS demonstrate decreased amplitudes of the SNAPs and CMAPs with slightly slow CVs. Nerve biopsy reveals a loss of myelinated fibers and giant axons that are filled with 10-nm neurofilaments. Hexacarbon exposure leads to covalent cross-linking between axonal neurofilaments that result in their aggregation, impaired axonal transport, swelling of the axons, and eventual axonal degeneration.


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InternalMed_Harrison. Lead neuropathy is uncommon, but it can be seen in children who accidentally ingest lead-based paints in older buildings and in industrial workers exposed to lead-containing products. The most common presentation of lead poisoning is an encephalopathy; however, symptoms and signs of a primarily motor neuropathy can also occur. The neuropathy is characterized by an insidious and progressive onset of weakness usually beginning in the arms, in particular involving the wrist and finger extensors, resembling a radial neuropathy. Sensation is generally preserved; however, the autonomic nervous system can be affected. Laboratory investigation can reveal a microcytic hypo-chromic anemia with basophilic stippling of erythrocytes, an elevated serum lead level, and an elevated serum coproporphyrin level. A 24-h urine collection demonstrates elevated levels of lead excretion. The NCS may reveal reduced CMAP amplitudes, while the SNAPs are typically normal. The pathogenic basis may be related to


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InternalMed_Harrison. level. A 24-h urine collection demonstrates elevated levels of lead excretion. The NCS may reveal reduced CMAP amplitudes, while the SNAPs are typically normal. The pathogenic basis may be related to abnormal porphyrin metabolism. The most important principle of management is to remove the source of the exposure. Chelation therapy with calcium disodium ethylene-diaminetetraacetic acid (EDTA), British anti-Lewisite (BAL), and penicillamine also demonstrates variable efficacy.


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InternalMed_Harrison. Mercury toxicity may occur as a result of exposure to either organic or inorganic mercurials. Mercury poisoning presents with paresthesias in hands and feet that progress proximally and may involve the face and tongue. Motor weakness can also develop. CNS symptoms often overshadow the neuropathy. EDx shows features of a primarily axonal sensorimotor polyneuropathy. The primary site of neuromuscular pathology appears to be the dorsal root ganglia. The mainstay of treatment is removing the source of exposure.


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InternalMed_Harrison. Thallium can exist in a monovalent or trivalent form and is primarily used as a rodenticide. The toxic neuropathy usually manifests as burning paresthesias of the feet, abdominal pain, and vomiting. Increased thirst, sleep disturbances, and psychotic behavior may be noted. Within the first week, patients develop pigmentation of the hair, an acne-like rash in the malar area of the face, and hyperreflexia. By the second and third week, autonomic instability with labile heart rate and blood pressure may be seen. Hyporeflexia and alopecia also occur but may not be evident until the third or fourth week following exposure. With severe intoxication, proximal weakness and involvement of the cranial nerves can occur. Some patients require mechanical ventilation due to respiratory muscle involvement. The lethal dose of thallium is variable, ranging from 8 to 15 mg/kg body weight. Death can result in less than 48 h following a particularly large dose. NCS demonstrate features of a primarily


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InternalMed_Harrison. The lethal dose of thallium is variable, ranging from 8 to 15 mg/kg body weight. Death can result in less than 48 h following a particularly large dose. NCS demonstrate features of a primarily axonal sensorimotor polyneuropathy. With acute intoxication, potassium ferric ferrocyanide II may be effective in preventing absorption of thallium from the gut. However, there may be no benefit once thallium has been absorbed. Unfortunately, chelating agents are not very efficacious. Adequate diuresis is essential to help eliminate thallium from the body without increasing tissue availability from the serum.


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InternalMed_Harrison. Arsenic is another heavy metal that can cause a toxic sensorimotor polyneuropathy. The neuropathy manifests 5–10 days after ingestion of arsenic and progresses for several weeks, sometimes mimicking GBS. The presenting symptoms are typically an abrupt onset of abdominal discomfort, nausea, vomiting, pain, and diarrhea followed within several days by burning pain in the feet and hands. Examination of the skin can be helpful in the diagnosis as the loss of the superficial epidermal layer results in patchy regions of increased or decreased pigmentation on the skin several weeks after an acute exposure or with chronic low levels of ingestion. Mee’s lines, which are transverse lines at the base of the fingernails and toenails, do not become evident until 1 or 2 months after the exposure. Multiple Mee’s lines may be seen in patients with long fingernails who have had chronic exposure to arsenic. Mee’s lines are not specific for arsenic toxicity as they can also be seen following thallium


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InternalMed_Harrison. Mee’s lines may be seen in patients with long fingernails who have had chronic exposure to arsenic. Mee’s lines are not specific for arsenic toxicity as they can also be seen following thallium poisoning. Because arsenic is cleared from blood rapidly, the serum concentration of arsenic is not diagnostically helpful. However, arsenic levels are increased in the urine, hair, and fingernails of patients exposed to arsenic. Anemia with stippling of erythrocytes is common, and occasionally pancytopenia and aplastic anemia can develop. Increased CSF protein levels without pleocytosis can be seen; this can lead to misdiagnosis as GBS. NCS are usually suggestive of an axonal sensorimotor polyneuropathy; however, demyelinating features can be present. Chelation therapy with BAL has yielded inconsistent results; therefore, it is not generally recommended.


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InternalMed_Harrison. Pernicious anemia is the most common cause of cobalamin deficiency. Other causes include dietary avoidance (vegetarians), gastrectomy, gastric bypass surgery, inflammatory bowel disease, pancreatic insufficiency, bacterial overgrowth, and possibly histamine-2 blockers and proton pump inhibitors. An underappreciated cause of cobalamin deficiency is food-cobalamin malabsorption. This typically occurs in older individuals and results from an inability to adequately absorb 2690 cobalamin in food protein. No apparent cause of deficiency is identified in a significant number of patients with cobalamin deficiency. The use of nitrous oxide as an anesthetic agent or as a recreational drug can produce acute cobalamin deficiency neuropathy and subacute combined degeneration. Complaints of numb hands typically appear before lower extremity paresthesias are noted. A preferential large-fiber sensory loss affecting proprioception and vibration with sparing of small-fiber modalities is present; an


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InternalMed_Harrison. typically appear before lower extremity paresthesias are noted. A preferential large-fiber sensory loss affecting proprioception and vibration with sparing of small-fiber modalities is present; an unsteady gait reflects sensory ataxia. These features, coupled with diffuse hyperreflexia and absent Achilles reflexes, should always focus attention on the possibility of cobalamin deficiency. Optic atrophy and, in severe cases, behavioral changes ranging from mild irritability and forgetfulness to severe dementia and frank psychosis may appear. The full clinical picture of subacute combined degeneration is uncommon. CNS manifestations, especially pyramidal tract signs, may be missing, and in fact some patients may only exhibit symptoms of peripheral neuropathy. EDx shows an axonal sensorimotor neuropathy. CNS involvement produces abnormal somatosensory and visual evoked potential latencies. The diagnosis is confirmed by finding reduced serum cobalamin levels. In up to 40% of patients,


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InternalMed_Harrison. neuropathy. CNS involvement produces abnormal somatosensory and visual evoked potential latencies. The diagnosis is confirmed by finding reduced serum cobalamin levels. In up to 40% of patients, anemia and macrocytosis are lacking. Serum methylmalonic acid and homocysteine, the metabolites that accumulate when cobalamin-dependent reactions are blocked, are elevated. Antibodies to intrinsic factor are present in approximately 60%, and antiparietal cell antibodies in about 90%, of individuals with pernicious anemia. Cobalamin deficiency can be treated with various regimens of cobalamin. One typical regimen consists of 1000 μg cyanocobalamin IM weekly for 1 month and monthly thereafter. Patients with food cobalamin malabsorption can absorb free cobalamin and therefore can be treated with oral cobalamin supplementation. An oral cobalamin dose of 1000 μg per day should be sufficient. Treatment for cobalamin deficiency usually does not completely reverse the clinical manifestations, and at


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InternalMed_Harrison. cobalamin supplementation. An oral cobalamin dose of 1000 μg per day should be sufficient. Treatment for cobalamin deficiency usually does not completely reverse the clinical manifestations, and at least 50% of patients exhibit some permanent neurologic deficit.


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InternalMed_Harrison. Thiamine (vitamin B1) deficiency is an uncommon cause of peripheral neuropathy in developed countries. It is now most often seen as a consequence of chronic alcohol abuse, recurrent vomiting, total parenteral nutrition, and bariatric surgery. Thiamine deficiency polyneuropathy can occur in normal, healthy young adults who do not abuse alcohol but who engage in inappropriately restrictive diets. Thiamine is water-soluble. It is present in most animal and plant tissues, but the greatest sources are unrefined cereal grains, wheat germ, yeast, soybean flour, and pork. Beriberi means “I can’t, I can’t” in Singhalese, the language of natives of what was once part of the Dutch East Indies (now Sri Lanka). Dry beriberi refers to neuropathic symptoms. The term wet beriberi is used when cardiac manifestations predominate (in reference to edema). Beriberi was relatively uncommon until the late 1800s when it became widespread among people for whom rice was a dietary mainstay. This epidemic was


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InternalMed_Harrison. predominate (in reference to edema). Beriberi was relatively uncommon until the late 1800s when it became widespread among people for whom rice was a dietary mainstay. This epidemic was due to a new technique of processing rice that removed the germ from the rice shaft, rendering the so-called polished rice deficient in thiamine and other essential nutrients.


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InternalMed_Harrison. Symptoms of neuropathy follow prolonged deficiency. These begin with mild sensory loss and/or burning dysesthesias in the toes and feet and aching and cramping in the lower legs. Pain may be the predominant symptom. With progression, patients develop features of a nonspecific generalized polyneuropathy, with distal sensory loss in the feet and hands.


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InternalMed_Harrison. Blood and urine assays for thiamine are not reliable for diagnosis of deficiency. Erythrocyte transketolase activity and the percentage increase in activity (in vitro) following the addition of thiamine pyrophosphate (TPP) may be more accurate and reliable. EDx shows nonspecific findings of an axonal sensorimotor polyneuropathy. When a diagnosis of thiamine deficiency is made or suspected, thiamine replacement should be provided until proper nutrition is restored. Thiamine is usually given intravenously or intramuscularly at a dose of 100 mg/d. Although cardiac manifestations show a striking response to thiamine replacement, neurologic improvement is usually more variable and less dramatic.


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InternalMed_Harrison. The term vitamin E is usually used for a-tocopherol, the most active of the four main types of vitamin E. Because vitamin E is present in animal fat, vegetable oils, and various grains, deficiency is usually due to factors other than insufficient intake. Vitamin E deficiency usually occurs secondary to lipid malabsorption or in uncommon disorders of vitamin E transport. One hereditary disorder is abetalipoproteinemia, a rare autosomal dominant disorder characterized by steatorrhea, pigmentary retinopathy, acanthocytosis, and progressive ataxia. Patients with cystic fibrosis may also have vitamin E deficiency secondary to steatorrhea. There are genetic forms of isolated vitamin E deficiency not associated with lipid malabsorption. Vitamin E deficiency may also occur as a consequence of various cholestatic and hepatobiliary disorders as well as short-bowel syndromes resulting from the surgical treatment of intestinal disorders.


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InternalMed_Harrison. Clinical features may not appear until many years after the onset of deficiency. The onset of symptoms tends to be insidious, and progression is slow. The main clinical features are spinocerebellar ataxia and polyneuropathy, thus resembling Friedreich’s ataxia or other spinocerebellar ataxias. Patients manifest progressive ataxia and signs of posterior column dysfunction, such as impaired joint position and vibratory sensation. Because of the polyneuropathy, there is hyporeflexia, but plantar responses may be extensor as a result of the spinal cord involvement. Other neurologic manifestations may include ophthalmoplegia, pigmented retinopathy, night blindness, dysarthria, pseudoathetosis, dystonia, and tremor. Vitamin E deficiency may present as an isolated polyneuropathy, but this is very rare. The yield of checking serum vitamin E levels in patients with isolated polyneuropathy is extremely low, and this test should not be part of routine practice.


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InternalMed_Harrison. Diagnosis is made by measuring a-tocopherol levels in the serum. EDx shows features of an axonal neuropathy. Treatment is replacement with oral vitamin E, but high doses are not needed. For patients with isolated vitamin E deficiency, treatment consists of 1500–6000 IU/d in divided doses. Vitamin B6, or pyridoxine, can produce neuropathic manifestations from both deficiency and toxicity. Vitamin B6 toxicity was discussed above. Vitamin B6 deficiency is most commonly seen in patients treated with isoniazid or hydralazine. The polyneuropathy of vitamin B6 is nonspecific, manifesting as a generalized axonal sensorimotor polyneuropathy. Vitamin B6 deficiency can be detected by direct assay. Vitamin B6 supplementation with 50–100 mg/d is suggested for patients being treated with isoniazid or hydralazine. This same dose is appropriate for replacement in cases of nutritional deficiency.


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InternalMed_Harrison. Pellagra is produced by deficiency of niacin. Although pellagra may be seen in alcoholics, this disorder has essentially been eradicated in most Western countries by means of enriching bread with niacin. Nevertheless, pellagra continues to be a problem in a number of underdeveloped regions, particularly in Asia and Africa, where corn is the main source of carbohydrate. Neurologic manifestations are variable; abnormalities can develop in the brain and spinal cord as well as peripheral nerves. When peripheral nerves are involved, the neuropathy is usually mild and resembles beriberi. Treatment is with niacin 40–250 mg/d.


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InternalMed_Harrison. A syndrome that has only recently been described is myeloneuropathy secondary to copper deficiency. Most patients present with lower limb paresthesias, weakness, spasticity, and gait difficulties. Large-fiber sensory function is impaired, reflexes are brisk, and plantar responses are extensor. In some cases, light touch and pinprick sensation are affected, and NCS indicate sensorimotor axonal polyneuropathy in addition to myelopathy.


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InternalMed_Harrison. Hematologic abnormalities are a known complication of copper deficiency; these can include microcytic anemia, neutropenia, and occasionally pancytopenia. Because copper is absorbed in the stomach and proximal jejunum, many cases of copper deficiency are in the setting of prior gastric surgery. Excess zinc is an established cause of copper deficiency. Zinc upregulates enterocyte production of metallothionine, which results in decreased absorption of copper. Excessive dietary zinc supplements or denture cream containing zinc can produce this clinical picture. Other potential causes of copper deficiency include malnutrition, prematurity, total parenteral nutrition, and ingestion of copper-chelating agents.


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InternalMed_Harrison. Following oral or IV copper replacement, some patients show neurologic improvement, but this may take many months or not occur at all. Replacement consists of oral copper sulfate or gluconate 2 mg one to three times a day. If oral copper replacement is not effective, elemental copper in the copper sulfate or copper chloride forms can be given as 2 mg IV daily for 3–5 days, then weekly for 1–2 months until copper levels normalize. Thereafter, oral daily copper therapy can be resumed. In contrast to the neurologic manifestations, most of the hematologic indices completely normalize in response to copper replacement therapy.


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InternalMed_Harrison. Polyneuropathy may occur following gastric surgery for ulcer, cancer, or weight reduction. This usually occurs in the context of rapid, significant weight loss and recurrent, protracted vomiting. The clinical picture is one of acute or subacute sensory loss and weakness. Neuropathy following weight loss surgery usually occurs in the first several months after surgery. Weight reduction surgical procedures include gastrojejunostomy, gastric stapling, vertical banded gastroplasty, and gastrectomy with Roux-en-Y anastomosis. The initial manifestations are usually numbness and paresthesias in the feet. In many cases, no specific nutritional deficiency factor is identified.


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InternalMed_Harrison. Management consists of parenteral vitamin supplementation, especially including thiamine. Improvement has been observed following supplementation, parenteral nutritional support, and reversal of the surgical bypass. The duration and severity of deficits before identification and treatment of neuropathy are important predictors of final outcome.


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InternalMed_Harrison. CSPN is a diagnosis of exclusion, established after a careful medical, family, and social history; neurologic examination; and directed laboratory testing. Despite extensive evaluation, the cause of polyneuropathy in as many as 50% of all patients is idiopathic. CSPN should be considered a distinct diagnostic subset of peripheral neuropathy. The onset of CSPN is predominantly in the sixth and seventh decades. Patients complain of distal numbness, tingling, and often burning pain that invariably begins in the feet and may eventually involve the fingers and hands. Patients exhibit a distal sensory loss to pinprick, touch, and vibration in the toes and feet, and occasionally in the fingers. It is uncommon to see significant proprioception deficits, even though patients may complain of gait unsteadiness. However, tandem gait may be abnormal in a minority of cases. Neither subjective nor objective evidence of weakness is a prominent feature. Most patients have evidence of both largeand


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InternalMed_Harrison. unsteadiness. However, tandem gait may be abnormal in a minority of cases. Neither subjective nor objective evidence of weakness is a prominent feature. Most patients have evidence of both largeand small-fiber loss on neurologic exam and EDx. Approximately 10% of patients have only evidence of small-fiber involvement. The ankle muscle stretch reflex is frequently absent, but in cases with predominantly small-fiber loss, this may be preserved. The EDx findings range from isolated sensory nerve action potential abnormalities (usually with loss of amplitude), to evidence for an axonal sensorimotor neuropathy, to a completely normal study (if primarily small fibers are involved). Therapy primarily involves the control of neuropathic pain (Table 459-6) if present. These drugs should not be used if the patient has only numbness and tingling but no pain.


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InternalMed_Harrison. Although no treatment is available that can reverse an idiopathic distal peripheral neuropathy, the prognosis is good. Progression often does not occur or is minimal, with sensory symptoms and signs pro-2691 gressing proximally up to the knees and elbows. The disorder does not lead to significant motor disability over time. The relatively benign course of this disorder should be explained to patients. CTS is a compression of the median nerve in the carpal tunnel at the wrist. The median nerve enters the hand through the carpal tunnel by coursing under the transverse carpal ligament. The symptoms of


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InternalMed_Harrison. CTS consist of numbness and paresthesias variably in the thumb, index, middle, and half of the ring finger. At times, the paresthesias can include the entire hand and extend into the forearm or upper arm or can be isolated to one or two fingers. Pain is another common symptom and can be located in the hand and forearm and, at times, in the proximal arm. CTS is common and often misdiagnosed as thoracic outlet syndrome. The signs of CTS are decreased sensation in the median nerve distribution; reproduction of the sensation of tingling when a percussion hammer is tapped over the wrist (Tinel’s sign) or the wrist is flexed for 30–60 s (Phalen’s sign); and weakness of thumb opposition and abduction. EDx is extremely sensitive and shows slowing of sensory and, to a lesser extent, motor median potentials across the wrist. Treatment options consist of avoidance of precipitating activities; control of underlying systemic-associated conditions if present; nonsteroidal anti-inflammatory


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InternalMed_Harrison. median potentials across the wrist. Treatment options consist of avoidance of precipitating activities; control of underlying systemic-associated conditions if present; nonsteroidal anti-inflammatory medications; neutral (volar) position wrist splints, especially for night use; glucocorticoid/anesthetic injection into the carpal tunnel; and surgical decompression by dividing the transverse carpal ligament. The surgical option should be considered if there is a poor response to nonsurgical treatments; if there is thenar muscle atrophy and/or weakness; and if there are significant denervation potentials on EMG.


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InternalMed_Harrison. Other proximal median neuropathies are very uncommon and include the pronator teres syndrome and anterior interosseous neuropathy. These often occur as a partial form of brachial plexitis.


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InternalMed_Harrison. The ulnar nerve passes through the condylar groove between the medial epicondyle and the olecranon. Symptoms consist of paresthesias, tingling, and numbness in the medial hand and half of the fourth and the entire fifth fingers, pain at the elbow or forearm, and weakness. Signs consist of decreased sensation in an ulnar distribution, Tinel’s sign at the elbow, and weakness and atrophy of ulnar-innervated hand muscles. The Froment sign indicates thumb adductor weakness and consists of flexion of the thumb at the interphalangeal joint when attempting to oppose the thumb against the lateral border of the second digit. EDx may show slowing of ulnar motor NCV across the elbow with prolonged ulnar sensory latencies. Treatment consists of avoiding aggravating factors, using elbow pads, and surgery to decompress the nerve in the cubital tunnel. Ulnar neuropathies can also rarely occur at the wrist in the ulnar (Guyon) canal or in the hand, usually after trauma.


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InternalMed_Harrison. The radial nerve winds around the proximal humerus in the spiral groove and proceeds down the lateral arm and enters the forearm, dividing into the posterior interosseous nerve and superficial nerve. The symptoms and signs consist of wristdrop; finger extension weakness; thumb abduction weakness; and sensory loss in the dorsal web between the thumb and index finger. Triceps and brachioradialis strength is often normal, and triceps reflex is often intact. Most cases of radial neuropathy are transient compressive (neuropraxic) injuries that recover spontaneously in 6–8 weeks. If there has been prolonged compression and severe axonal damage, it may take several months to recover. Treatment consists of cock-up wrist and finger splints, avoiding further compression, and physical therapy to avoid flexion contracture. If there is no improvement in 2–3 weeks, an EDx study is recommended to confirm the clinical diagnosis and determine the degree of severity.


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InternalMed_Harrison. 2692 LATERAL FEMORAL CUTANEOUS NEUROPATHY (MERALGIA PARESTHETICA) The lateral femoral cutaneous nerve arises from the upper lumbar plexus (spinal levels L2/3), crosses through the inguinal ligament near its attachment to the iliac bone, and supplies sensation to the anterior lateral thigh. The neuropathy affecting this nerve is also known as meralgia paresthetica. Symptoms and signs consist of paresthesias, numbness, and occasionally pain in the lateral thigh. Symptoms are increased by standing or walking and are relieved by sitting. There is normal strength, and knee reflexes are intact. The diagnosis is clinical, and further tests usually are not performed. EDx is only needed to rule out lumbar plexopathy, radiculopathy, or femoral neuropathy. If the symptoms and signs are classic, EMG is not necessary. Symptoms often resolve spontaneously over weeks or months, but the patient may be left with permanent numbness. Treatment consists of weight loss and avoiding tight belts. Analgesics


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InternalMed_Harrison. not necessary. Symptoms often resolve spontaneously over weeks or months, but the patient may be left with permanent numbness. Treatment consists of weight loss and avoiding tight belts. Analgesics in the form of a lidocaine patch, nonsteroidal agents, and occasionally medications for neuropathic pain can be used (Table 459-6). Rarely, locally injecting the nerve with an anesthetic can be tried. There is no role for surgery.


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InternalMed_Harrison. Femoral neuropathies can arise as complications of retroperitoneal hematoma, lithotomy positioning, hip arthroplasty or dislocation, iliac artery occlusion, femoral arterial procedures, infiltration by hematogenous malignancy, penetrating groin trauma, pelvic surgery including hysterectomy and renal transplantation, and diabetes (a partial form of lumbosacral diabetic plexopathy); some cases are idiopathic. Patients with femoral neuropathy have difficulty extending their knee and flexing the hip. Sensory symptoms occurring either on the anterior thigh and/or medial leg occur in only half of reported cases. A prominent painful component is the exception rather than the rule, may be delayed, and is often self-limited in nature. The quadriceps (patellar) reflex is diminished.


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InternalMed_Harrison. Sciatic neuropathies commonly complicate hip arthroplasty, pelvic procedures in which patients are placed in a prolonged lithotomy position, trauma, hematomas, tumor infiltration, and vasculitis. In addition, many sciatic neuropathies are idiopathic. Weakness may involve all motions of the ankles and toes as well as flexion of the leg at the knee; abduction and extension of the thigh at the hip are spared. Sensory loss occurs in the entire foot and the distal lateral leg. The ankle jerk and on occasion the internal hamstring reflex are diminished or more typically absent on the affected side. The peroneal subdivision of the sciatic nerve is typically involved disproportionately to the tibial counterpart. Thus, patients may have only ankle dorsiflexion and eversion weakness with sparing of knee flexion, ankle inversion, and plantar flexion; these features can lead to misdiagnosis of a common peroneal neuropathy.


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InternalMed_Harrison. The sciatic nerve divides at the distal femur into the tibial and peroneal nerve. The common peroneal nerve passes posterior and laterally around the fibular head, under the fibular tunnel. It then divides into the superficial peroneal nerve, which supplies the ankle evertor muscles and sensation over the anterolateral distal leg and dorsum of the foot, and the deep peroneal nerve, which supplies ankle dorsiflexors and toe extensor muscles and a small area of sensation dorsally in the area of the first and second toes.


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InternalMed_Harrison. Symptoms and signs consist of footdrop (ankle dorsiflexion, toe extension, and ankle eversion weakness) and variable sensory loss, which may involve the superficial and deep peroneal pattern. There is usually no pain. Onset may be on awakening in the morning. Peroneal neuropathy needs to be distinguished from L5 radiculopathy. In L5 radiculopathy, ankle invertors and evertors are weak and needle EMG reveals denervation. EDx can help localize the lesion. Peroneal motor conduction velocity shows slowing and amplitude drop across the fibular head. Management consists of rapid weight loss and avoiding leg crossing. Footdrop is treated with an ankle brace. A knee pad can be worn over the lateral knee to avoid further compression. Most cases spontaneously resolve over weeks or months.


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InternalMed_Harrison. Radiculopathies are most often due to compression from degenerative joint disease and herniated disks, but there are a number of unusual etiologies (Table 459-9). Degenerative spine disease affects a number of different structures, which narrow the diameter of the neural foramen or canal of the spinal column and compromise nerve root integrity; these are discussed in detail in Chap. 22. The brachial plexus is composed of three trunks (upper, middle, and lower), with two divisions (anterior and posterior) per trunk (Fig. 459-2). Subsequently, the trunks divide into three cords (medial, lateral, and posterior), and from these arise the multiple terminal nerves innervating the arm. The anterior primary rami of C5 and C6 fuse to form the upper trunk; the anterior primary ramus of C7 continues as the middle trunk, while the anterior rami of C8 and T1 join to form the lower trunk. There are several disorders commonly associated with brachial plexopathy.


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InternalMed_Harrison. Immune-Mediated Brachial Plexus Neuropathy Immune-mediated brachial plexus neuropathy (IBPN) goes by various terms, including acute brachial plexitis, neuralgic amyotrophy, and Parsonage-Turner syndrome. IBPN usually presents with an acute onset of severe pain in the shoulder region. The intense pain usually lasts several days to a few weeks, but a dull ache can persist. Individuals who are affected may not appreciate weakness of the arm early in the course because the pain limits movement. However, as the pain dissipates, weakness and often sensory loss are appreciated. Attacks can occasionally recur.


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InternalMed_Harrison. Clinical findings are dependent on the distribution of involvement (e.g., specific trunk, divisions, cords, or terminal nerves). The most common pattern of IBPN involves the upper trunk or a single or multiple mononeuropathies primarily involving the suprascapular, long thoracic, or axillary nerves. Additionally, the phrenic and anterior interosseous nerves may be concomitantly affected. Any of these nerves may also be affected in isolation. EDx is useful to confirm and localize the site(s) of involvement. Empirical treatment of severe pain with glucocorticoids is often used in the acute period. Brachial Plexopathies Associated with Neoplasms Neoplasms involving the brachial plexus may be primary nerve tumors, local cancers expanding into the plexus (e.g., Pancoast lung tumor or lymphoma),


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InternalMed_Harrison. Brachial Plexopathies Associated with Neoplasms Neoplasms involving the brachial plexus may be primary nerve tumors, local cancers expanding into the plexus (e.g., Pancoast lung tumor or lymphoma), Causes of raDiCuLopathy by extradural mass (e.g., meningioma, metastatic tumor, hematoma, abscess) nerve tumor (e.g., neurofibroma, schwannoma, neurinoma) spread of tumor (e.g., prostate cancer) (Lyme disease, herpes zoster, cytomegalovirus, syphilis, schistosomiasis, strongyloides) FIGURE 459-2 Brachial plexus anatomy. L, lateral; M, medial; P, posterior. (From J Goodgold: Anatomical Correlates of Clinical Electromyography.


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InternalMed_Harrison. Baltimore, Williams and Wilkins, 1974, p. 126, with permission.) and metastatic tumors. Primary brachial plexus tumors are less common than the secondary tumors and include schwannomas, neurinomas, and neurofibromas. Secondary tumors affecting the brachial plexus are more common and are always malignant. These may arise from local tumors, expanding into the plexus. For example, a Pancoast tumor of the upper lobe of the lung may invade or compress the lower trunk, whereas a primary lymphoma arising from the cervical or axillary lymph nodes may also infiltrate the plexus. Pancoast tumors typically present as an insidious onset of pain in the upper arm, sensory disturbance in the medial aspect of the forearm and hand, and weakness and atrophy of the intrinsic hand muscles along with an ipsilateral Horner’s syndrome. Chest computed tomography (CT) scans or magnetic resonance imaging (MRI) can demonstrate extension of the tumor into the plexus. Metastatic involvement of the brachial plexus


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InternalMed_Harrison. Horner’s syndrome. Chest computed tomography (CT) scans or magnetic resonance imaging (MRI) can demonstrate extension of the tumor into the plexus. Metastatic involvement of the brachial plexus may occur with spread of breast cancer into the axillary lymph nodes with local spread into the nearby nerves.


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InternalMed_Harrison. Perioperative Plexopathies (Median Sternotomy) The most common surgical procedures associated with brachial plexopathy as a complication are those that involve median sternotomies (e.g., open-heart surgeries and thoracotomies). Brachial plexopathies occur in as many as 5% of patients following a median sternotomy and typically affect the lower trunk. Thus, individuals manifest with sensory disturbance affecting the medial aspect of forearm and hand along with weakness of the intrinsic hand muscles. The mechanism is related to the stretch of the lower trunk, so most individuals who are affected recover within a few months.


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InternalMed_Harrison. Lumbosacral Plexus The lumbar plexus arises from the ventral primary rami of the first to the fourth lumbar spinal nerves (Fig. 459-3). These nerves pass downward and laterally from the vertebral column within the psoas major muscle. The femoral nerve derives from the dorsal branches of the second to the fourth lumbar ventral rami. The obturator nerve arises from the ventral branches of the same lumbar rami. The lumbar plexus communicates with the sacral plexus by the lumbosacral trunk, which contains some fibers from the fourth and all of the fibers from the fifth lumbar ventral rami (Fig. 459-4).


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InternalMed_Harrison. The sacral plexus is the part of the lumbosacral plexus that is formed by the union of the lumbosacral trunk with the ventral rami of the first to fourth sacral nerves. The plexus lies on the posterior and posterolateral wall of the pelvis with its components converging toward the sciatic notch. The lateral trunk of the sciatic nerve (which forms the common peroneal nerve) arises from the union of the dorsal branches of the lumbosacral trunk (L4, L5) and the dorsal branches of the S1 and S2 spinal nerve ventral rami. The medial trunk of the sciatic nerve (which forms the tibial nerve) derives from the ventral branches of the same ventral rami (L4-S2).


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InternalMed_Harrison. Plexopathies are typically recognized when motor, sensory, and if applicable, reflex deficits occur in multiple nerve and segmental distributions confined to one extremity. If localization within the lumbosacral plexus can be accomplished, designation as a lumbar plexopathy, a sacral plexopathy, a lumbosacral trunk lesion, or a panplexopathy is the best localization that can be expected. Although lumbar plexopathies may be bilateral, usually occurring in a stepwise and chronologically dissociated manner, sacral plexopathies are more likely to behave in this manner due to their closer anatomic proximity. The differential diagnosis of plexopathy includes disorders of the conus medullaris and cauda equina (polyradiculopathy). If there is a paucity of pain and sensory involvement, motor neuron disease should be considered as well.


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InternalMed_Harrison. The causes of lumbosacral plexopathies are listed in Table 459-10. Diabetic radiculopathy (discussed above) is a fairly common cause of painful leg weakness. Lumbosacral plexopathies are a well-recognized T12 Lateral femoral cutaneous n. Femoral n. T12 Iliohypogastric n. Ilioinguinal n. Genitofemoral n. Obturator n. Lumbosacral trunk L1 L2 L3 L4 L5


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InternalMed_Harrison. T12 Lateral femoral cutaneous n. Femoral n. T12 Iliohypogastric n. Ilioinguinal n. Genitofemoral n. Obturator n. Lumbosacral trunk L1 L2 L3 L4 L5 FIGURE 459-3 Lumbar plexus. Posterior divisions are in orange, and anterior divisions are in yellow. (From J Goodgold: Anatomical Correlates of Clinical Electromyography.Baltimore, Williams and Wilkins, 1974, p. 126, with permission.) complication of retroperitoneal hemorrhage. Various primary and metastatic malignancies can affect the lumbosacral plexus as well; these include carcinoma of the cervix, endometrium, and ovary; osteosarcoma; testicular cancer; multiple myeloma; lymphoma; acute myelogenous leukemia; colon cancer; squamous cell carcinoma of the rectum; adenocarcinoma of unknown origin; and intraneural spread of prostate cancer.


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InternalMed_Harrison. The treatment for various malignancies is often radiation therapy, the field of which may include parts of the brachial plexus. It can be difficult in such situations to determine if a new brachial or lumbosacral plexopathy is related to tumor within the plexus or from radiation-induced nerve damage. Radiation can be associated with LumBosaCraL pLexopathies: etioLoGies


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InternalMed_Harrison. LumBosaCraL pLexopathies: etioLoGies L4 L5 S1 S2 S3 S4 To sphincter ani externus Pudendal Inferior gluteal Superior gluteal Common peroneal Tibial FIGURE 459-4 Lumbosacral plexus. Posterior divisions are in orange, and anterior divisions are in yellow. (From J Goodgold: Anatomical Correlates of Clinical Electromyography. Baltimore, Williams and Wilkins, 1974, p. 126, with permission.) Guillain-Barré syndrome and other immune-mediated Neuropathies Stephen L. Hauser, Anthony A. Amato GUILLAIN-BARRÉ SYNDROME 460 microvascular abnormalities and fibrosis of surrounding tissues, which can damage the axons and the Schwann cells. Radiation-induced plexopathy can develop months or years following therapy and is dose dependent.


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InternalMed_Harrison. Tumor invasion is usually painful and more commonly affects the lower trunk, whereas radiation injury is often painless and affects the upper trunk. Imaging studies such as MRI and CT scans are useful but can be misleading with small microscopic invasion of the plexus. EMG can be informative if myokymic discharges are appreciated, as this finding strongly suggests radiation-induced damage. Most patients with plexopathies will undergo both imaging with MRI and EDx evaluations. Severe pain from acute idiopathic lumbosacral plexopathy may respond to a short course of glucocorticoids. Guillain-Barré syndrome (GBS) is an acute, frequently severe, and fulminant polyradiculoneuropathy that is autoimmune in nature. It occurs year-round at a rate of between 1 and 4 cases per 100,000 annually; in the United States, ~5000–6000 cases occur per year. Males are at slightly higher risk for GBS than females, and in Western countries, adults are more frequently affected than children.


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InternalMed_Harrison. Clinical Manifestations GBS manifests as a rapidly evolving areflexic motor paralysis with or without sensory disturbance. The usual pattern is an ascending paralysis that may be first noticed as rubbery legs. Weakness typically evolves over hours to a few days and is frequently accompanied by tingling dysesthesias in the extremities. The legs are usually more affected than the arms, and facial diparesis is present in 50% of affected individuals. The lower cranial nerves are also frequently involved, causing bulbar weakness with difficulty handling secretions and maintaining an airway; the diagnosis in these patients may initially be mistaken for brainstem ischemia. Pain in the neck, shoulder, back, or diffusely over the spine is also common in the early stages of GBS, occurring in ~50% of patients. Most patients require hospitalization, and in different series, up to 30% require ventilatory assistance at some time during the illness. The need for mechanical ventilation is associated


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InternalMed_Harrison. patients. Most patients require hospitalization, and in different series, up to 30% require ventilatory assistance at some time during the illness. The need for mechanical ventilation is associated with more severe weakness on admission, a rapid tempo of progression, and the presence of facial and/or bulbar weakness during the first week of symptoms. Fever and constitutional symptoms are absent at the onset and, if present, cast doubt on the diagnosis. Deep tendon reflexes attenuate or disappear within the first few days of onset. Cutaneous sensory deficits (e.g., loss of pain and temperature sensation) are usually relatively mild, but functions subserved by large sensory fibers, such as deep tendon reflexes and proprioception, are more severely affected. Bladder dysfunction may occur in severe cases but is usually transient. If bladder dysfunction is a prominent feature and comes early in the course, diagnostic possibilities other than GBS should be considered, particularly spinal


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InternalMed_Harrison. severe cases but is usually transient. If bladder dysfunction is a prominent feature and comes early in the course, diagnostic possibilities other than GBS should be considered, particularly spinal cord disease. Once clinical worsening stops and the patient reaches a plateau (almost always within 4 weeks of onset), further progression is unlikely.


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InternalMed_Harrison. Autonomic involvement is common and may occur even in patients whose GBS is otherwise mild. The usual manifestations are loss of vasomotor control with wide fluctuation in blood pressure, postural hypotension, and cardiac dysrhythmias. These features require close monitoring and management and can be fatal. Pain is another common feature of GBS; in addition to the acute pain described above, a deep aching pain may be present in weakened muscles that patients liken to having overexercised the previous day. Other pains in GBS include dysesthetic pain in the extremities as a manifestation of sensory nerve fiber involvement. These pains are self-limited and often respond to standard analgesics (Chap. 18).


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InternalMed_Harrison. Several subtypes of GBS are recognized, as determined primarily by electrodiagnostic (Edx) and pathologic distinctions (Table 460-1). The most common variant is acute inflammatory demyelinating polyneuropathy (AIDP). Additionally, there are two axonal variants, which are often clinically severe—the acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN) subtypes. In addition, a range of limited or regional GBS syndromes are also encountered. Notable among these is the Miller Fisher syndrome (MFS), which presents as rapidly evolving ataxia and areflexia of limbs without weakness, and ophthalmoplegia, often with pupillary paralysis. The MFS variant accounts for ~5% of all cases and is strongly associated with antibodies to the ganglioside GQ1b (see “Immunopathogenesis,” below). Other regional variants of GBS include (1) pure sensory forms; (2) ophthalmoplegia with anti-GQ1b antibodies as part of severe motor-sensory GBS; (3) GBS with severe bulbar and


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InternalMed_Harrison. below). Other regional variants of GBS include (1) pure sensory forms; (2) ophthalmoplegia with anti-GQ1b antibodies as part of severe motor-sensory GBS; (3) GBS with severe bulbar and facial paralysis, sometimes associated with antecedent cytomegalovirus (CMV) infection and anti-GM2 antibodies; and (4) acute pandysautonomia (Chap. 454).


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InternalMed_Harrison. Antecedent Events Approximately 70% of cases of GBS occur 1–3 weeks after an acute infectious process, usually respiratory or gastrointestinal. Culture and seroepidemiologic techniques show that 20–30% of all cases occurring in North America, Europe, and Australia are preceded by infection or reinfection with Campylobacter jejuni. A similar proportion is preceded by a human herpes virus infection, often CMV or Epstein-Barr virus. Other viruses (e.g., HIV, hepatitis E) and also Mycoplasma pneumoniae have been identified as agents involved in antecedent infections, as have recent immunizations. The swine influenza vaccine, administered widely in the United States in 1976, is the most notable example. Influenza vaccines in use from 1992 to 1994, however, resulted in only one additional case of GBS per million persons vaccinated, and the more recent seasonal influenza vaccines appear to confer a GBS risk of <1 per million. Epidemiologic studies looking at H1N1 vaccination demonstrated at


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InternalMed_Harrison. of GBS per million persons vaccinated, and the more recent seasonal influenza vaccines appear to confer a GBS risk of <1 per million. Epidemiologic studies looking at H1N1 vaccination demonstrated at most only a slight increased risk of GBS. Meningococcal vaccinations (Menactra) does not appear to carry an increased risk. Older-type rabies vaccine, prepared in nervous system tissue, is implicated as a trigger of GBS in developing countries where it is still used; the mechanism is presumably immunization against neural antigens. GBS also occurs more frequently than can be attributed to chance alone in patients with lymphoma (including Hodgkin’s disease), in HIV-seropositive individuals, and in patients with systemic lupus erythematosus (SLE). C. jejuni has also been implicated in summer outbreaks of AMAN among children and young adults exposed to chickens in rural China.


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InternalMed_Harrison. Immunopathogenesis Several lines of evidence support an autoimmune basis for acute inflammatory demyelinating polyneuropathy (AIDP), the most common and best-studied type of GBS; the concept extends to all of the subtypes of GBS (Table 460-1).


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InternalMed_Harrison. It is likely that both cellular and humoral immune mechanisms contribute to tissue damage in AIDP. T cell activation is suggested by the finding that elevated levels of cytokines and cytokine receptors are present in serum (interleukin [IL] 2, soluble IL-2 receptor) and in cerebrospinal fluid (CSF) (IL-6, tumor necrosis factor α, interferon γ). AIDP is also closely analogous to an experimental T cell–mediated immunopathy designated experimental allergic neuritis (EAN). EAN is induced in laboratory animals by immune sensitization against protein fragments derived from peripheral nerve proteins, and in particular against the P2 protein. Based on analogy to EAN, it was initially thought that AIDP was likely to be primarily a T cell–mediated disorder; however, abundant data now suggest that autoantibodies directed against nonprotein determinants may be central to many cases.


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InternalMed_Harrison. Circumstantial evidence suggests that all GBS results from immune responses to nonself antigens (infectious agents, vaccines) that misdirect to host nerve tissue through a resemblance-of-epitope (molecular mimicry) mechanism (Fig. 460-1). The neural targets are likely to be glycoconjugates, specifically gangliosides (Table 460-2; Fig. 460-2). Gangliosides are complex glycosphingolipids that contain one or more sialic acid residues; various gangliosides participate in cell-cell interactions (including those between axons and glia), modulation of receptors, and regulation of growth. They are typically exposed on the plasma membrane of cells, rendering them susceptible to an antibody-mediated attack. Gangliosides and other glycoconjugates are present in large quantity in human nervous tissues and in key sites, such as nodes of Ranvier. Antiganglioside antibodies, most frequently to GM1, are common in GBS (20–50% of cases), particularly in AMAN and AMSAN and in those cases preceded by C.


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InternalMed_Harrison. and in key sites, such as nodes of Ranvier. Antiganglioside antibodies, most frequently to GM1, are common in GBS (20–50% of cases), particularly in AMAN and AMSAN and in those cases preceded by C. jejuni infection. Furthermore, isolates of C. jejuni from stool cultures of patients with GBS have surface glycolipid structures that antigenically cross react with gangliosides, including GM1, concentrated in human nerves. Sialic acid residues from pathogenic C. jejuni strains can also trigger activation of dendritic cells via signaling through a toll-like receptor (TLR4), promoting B cell differentiation and further amplifying humoral autoimmunity. Another line of evidence is derived from experience in Europe with parenteral use of purified bovine brain gangliosides for treatment of various neuropathic disorders. Between 5 and 15 days after injection, some recipients developed acute motor axonal GBS with high titers of anti-GM1 antibodies that recognized epitopes at nodes of Ranvier and


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InternalMed_Harrison. neuropathic disorders. Between 5 and 15 days after injection, some recipients developed acute motor axonal GBS with high titers of anti-GM1 antibodies that recognized epitopes at nodes of Ranvier and motor endplates. Experimentally, anti-GM1 antibodies can trigger complement-mediated injury at paranodal axon-glial junctions, disrupting the clustering of sodium channels and likely contributing to conduction block (see “Pathophysiology,” below).


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InternalMed_Harrison. CjCjCjjCIL 3,4,5,10 CD4 Antigen presenting cell B cell TCR MHC II B cell Schwann cell plasmalemma Blood/nerve barrier Ganglioside (GM-1 and others) Myelin sheath Plasma cell lgG Cj Cj Cj O A FIGURE 460-1 Postulated immunopathogenesis of Guillain-Barré syndrome (GBS) associated with Campylobacter jejuni infection.


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InternalMed_Harrison. B cells recognize glycoconjugates on C. jejuni (Cj) (triangles) that cross-react with ganglioside present on Schwann cell surface and subjacent peripheral nerve myelin. Some B cells, activated via a T cell–independent mechanism, secrete primarily IgM (not shown). Other B cells (upper left side) are activated via a partially T cell–dependent route and secrete primarily IgG; T cell help is provided by CD4 cells activated locally by fragments of Cj proteins that are presented on the surface of antigen-presenting cells (APCs). A critical event in the development of GBS is the escape of activated B cells from Peyer’s patches into regional lymph nodes. Activated T cells probably also function to assist in opening of the blood-nerve barrier, facilitating penetration of pathogenic autoantibodies. The earliest changes in myelin (right) consist of edema between myelin lamellae and vesicular disruption (shown as circular blebs) of the outermost myelin layers. These effects are associated with


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InternalMed_Harrison. The earliest changes in myelin (right) consist of edema between myelin lamellae and vesicular disruption (shown as circular blebs) of the outermost myelin layers. These effects are associated with activation of the C5b-C9 membrane attack complex and probably mediated by calcium entry; it is possible that the macrophage cytokine tumor necrosis factor (TNF) also participates in myelin damage. A, axon; B, B cell; MHC II, class II major histocompatibility complex molecule; O, oligodendrocyte; TCR, T cell receptor.


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InternalMed_Harrison. Abbreviations: CIDP-M, CIDP with a monoclonal gammopathy; MAG, myelin-associated glycoprotein; MGUS, monoclonal gammopathy of undetermined significance. Source: Modified from HJ Willison, N Yuki: Brain 125:2591, 2002. FIGURE 460-2 Glycolipids implicated as antigens in immune-mediated neuropathies. (Modified from HJ Willison, N Yuki: Brain 125: 2591, 2002.) Anti-GQ1b IgG antibodies are found in >90% of patients with MFS (Table 460-2; Fig. 460-2), and titers of IgG are highest early in the course. Anti-GQ1b antibodies are not found in other forms of GBS unless there is extraocular motor nerve involvement. A possible explanation for this association is that extraocular motor nerves are enriched in GQ1b gangliosides in comparison to limb nerves. In addition, a monoclonal anti-GQ1b antibody raised against C. jejuni isolated from a patient with MFS blocked neuromuscular transmission experimentally.


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InternalMed_Harrison. Taken together, these observations provide strong but still inconclusive evidence that autoantibodies play an important pathogenic role in GBS. Although antiganglioside antibodies have been studied most intensively, other antigenic targets may also be important. One report identified IgG antibodies against Schwann cells and neurons (nerve growth cone region) in some GBS cases. Proof that these antibodies are pathogenic requires that they be capable of mediating disease following direct passive transfer to naïve hosts; this has not yet been demonstrated, although one case of possible maternal-fetal transplacental transfer of GBS has been described.


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InternalMed_Harrison. In AIDP, an early step in the induction of tissue damage appears to be complement deposition along the outer surface of the Schwann cell. Activation of complement initiates a characteristic vesicular disintegration of the myelin sheath and also leads to recruitment of activated macrophages, which participate in damage to myelin and axons. In AMAN, the pattern is different in that complement is deposited along with IgG at the nodes of Ranvier along large motor axons. Interestingly, in cases of AMAN, antibodies against GD1a appear to have a fine specificity that favors binding to motor rather than sensory nerve roots, even though this ganglioside is expressed on both fiber types.


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InternalMed_Harrison. Pathophysiology In the demyelinating forms of GBS, the basis for flaccid paralysis and sensory disturbance is conduction block. This finding, demonstrable electrophysiologically, implies that the axonal connections remain intact. Hence, recovery can take place rapidly as remyelination occurs. In severe cases of demyelinating GBS, secondary axonal degeneration usually occurs; its extent can be estimated electro-physiologically. More secondary axonal degeneration correlates with a slower rate of recovery and a greater degree of residual disability. When a severe primary axonal pattern is encountered electrophysiologically, the implication is that axons have degenerated and become disconnected from their targets, specifically the neuromuscular junctions, and must therefore regenerate for recovery to take place. In motor axonal cases in which recovery is rapid, the lesion is thought to be localized to preterminal motor branches, allowing regeneration and reinnervation to take place


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InternalMed_Harrison. recovery to take place. In motor axonal cases in which recovery is rapid, the lesion is thought to be localized to preterminal motor branches, allowing regeneration and reinnervation to take place quickly. Alternatively, in mild cases, collateral sprouting and reinnervation from surviving motor axons near the neuromuscular junction may begin to reestablish physiologic continuity with muscle cells over a period of several months.


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InternalMed_Harrison. Laboratory Features CSF findings are distinctive, consisting of an elevated CSF protein level (1–10 g/L [100–1000 mg/dL]) without accompanying pleocytosis. The CSF is often normal when symptoms have been present for ≤48 h; by the end of the first week, the level of protein is usually elevated. A transient increase in the CSF white cell count (10–100/μL) occurs on occasion in otherwise typical GBS; however, a sustained CSF pleocytosis suggests an alternative diagnosis (viral myelitis) or a concurrent diagnosis such as unrecognized HIV infection, leukemia or lymphoma with infiltration of nerves, or neurosarcoidosis. Edx features are mild or absent in the early stages of GBS and lag behind the clinical evolution. In AIDP, the earliest features are prolonged F-wave latencies, prolonged distal latencies, and reduced amplitudes of compound muscle action potentials (CMAPs), probably owing to the predilection for involvement of nerve roots and distal motor nerve terminals early in the course.


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InternalMed_Harrison. latencies, and reduced amplitudes of compound muscle action potentials (CMAPs), probably owing to the predilection for involvement of nerve roots and distal motor nerve terminals early in the course. Later, slowing of conduction velocity, conduction block, and temporal dispersion may be appreciated (Table 460-1). Occasionally, sensory nerve action potentials (SNAPs) may be normal in the feet (e.g., sural nerve) when abnormal in the arms. This is also a sign that the patient does not have one of the more typical “length-dependent” polyneuropathies. In cases with primary axonal pathology, the principal Edx finding is reduced ampli-2697 tude of CMAPs (and also SNAPS with AMSAN) without conduction slowing or prolongation of distal latencies. Diagnosis GBS is a descriptive entity. The diagnosis of AIDP is made by recognizing the pattern of rapidly evolving paralysis with areflexia, absence of fever or other systemic symptoms, and characteristic antecedent events. In 2011, the Brighton


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InternalMed_Harrison. of AIDP is made by recognizing the pattern of rapidly evolving paralysis with areflexia, absence of fever or other systemic symptoms, and characteristic antecedent events. In 2011, the Brighton Collaboration developed a new set of case definitions for GBS in response to needs of epidemiologic studies of vaccination and assessing risks of GBS (Table 460-3). These criteria have subsequently been validated. Other disorders that may enter into the differential diagnosis include acute myelopathies (especially with prolonged back pain and sphincter disturbances); diphtheria (early oropharyngeal disturbances); Lyme polyradiculitis and other tick-borne paralyses; porphyria (abdominal pain, seizures, psychosis); vasculitic neuropathy (check erythrocyte sedimentation rate, described below); poliomyelitis (fever and meningismus common); West Nile virus; CMV polyradiculitis (in immunocompromised patients); critical illness neuropathy or myopathy; neuromuscular junction disorders such as


InternalMed_Harrison

InternalMed_Harrison. poliomyelitis (fever and meningismus common); West Nile virus; CMV polyradiculitis (in immunocompromised patients); critical illness neuropathy or myopathy; neuromuscular junction disorders such as myasthenia gravis and botulism (pupillary reactivity lost early); poisonings with organophosphates, thallium, or arsenic; paralytic shellfish poisoning; or severe hypophosphatemia (rare). Laboratory tests are helpful primarily to exclude mimics of GBS. Edx features may be minimal, and the CSF protein level may not rise until the end of the first week. If the diagnosis is strongly suspected, treatment should be initiated without waiting for evolution of the characteristic Edx and CSF findings to occur. GBS patients with risk factors for HIV or with CSF pleocytosis should have a serologic test for HIV.


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InternalMed_Harrison. In the vast majority of patients with GBS, treatment should be initiated as soon after diagnosis as possible. Each day counts; ~2 weeks after the first motor symptoms, it is not known whether immunotherapy is still effective. If the patient has already reached the plateau stage, then treatment probably is no longer indicated, unless the patient has severe motor weakness and one cannot exclude the possibility that an immunologic attack is still ongoing. Either high-dose intravenous immune globulin (IVIg) or plasmapheresis can be initiated, as they are equally effective for typical GBS. A combination of the two therapies is not significantly better than either alone. IVIg is often the initial therapy chosen because of its ease of administration and good safety record. Anecdotal data have also suggested that IVIg may be preferable to plasma exchange (PE) for the AMAN and MFS variants of GBS. IVIg is administered as five daily infusions for a total dose of 2 g/kg body weight. There is


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InternalMed_Harrison. also suggested that IVIg may be preferable to plasma exchange (PE) for the AMAN and MFS variants of GBS. IVIg is administered as five daily infusions for a total dose of 2 g/kg body weight. There is some evidence that GBS autoantibodies are neutralized by anti-idiotypic antibodies present in IVIg preparations, perhaps accounting for the therapeutic effect. A course of plasmapheresis usually consists of ~40–50 mL/kg PE four to five times over a week. Meta-analysis of randomized clinical trials indicates that treatment reduces the need for mechanical ventilation by nearly half (from 27% to 14% with PE) and increases the likelihood of full recovery at 1 year (from 55% to 68%). Functionally significant improvement may occur toward the end of the first week of treatment or may be delayed for several weeks. The lack of noticeable improvement following a course of IVIg or PE is not an indication to treat with the alternate treatment. However, there are occasional patients who are treated


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InternalMed_Harrison. several weeks. The lack of noticeable improvement following a course of IVIg or PE is not an indication to treat with the alternate treatment. However, there are occasional patients who are treated early in the course of GBS and improve, who then relapse within a month. Brief retreatment with the original therapy is usually effective in such cases. Glucocorticoids have not been found to be effective in GBS. Occasional patients with very mild forms of GBS, especially those who appear to have already reached a plateau when initially seen, may be managed conservatively without IVIg or PE.


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InternalMed_Harrison. In the worsening phase of GBS, most patients require monitoring in a critical care setting, with particular attention to vital capacity, heart rhythm, blood pressure, nutrition, deep vein thrombosis prophylaxis, cardiovascular status, early consideration (after 2 weeks BriGhtoN Criteria for DiaGNosis of GuiLLaiN-Barré syNDrome (GBs) aND miLLer fisher syNDrome Clinical case definitions for diagnosis of GBS Level 1 of diagnostic certainty Bilateral AND flaccid weakness of the limbs Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau Electrophysiologic findings consistent with GBS Cytoalbuminologic dissociation (i.e., elevation of CSF protein level above laboratory normal value AND CSF total white cell count <50 cells/μL) Absence of an identified alternative diagnosis for weakness Level 2 of diagnostic certainty Bilateral AND flaccid weakness of the limbs


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InternalMed_Harrison. Absence of an identified alternative diagnosis for weakness Level 2 of diagnostic certainty Bilateral AND flaccid weakness of the limbs Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau If CSF not collected or results not available, electrophysiologic studies consistent with GBS Absence of identified alternative diagnosis for weakness Level 3 of diagnostic certainty Bilateral and flaccid weakness of the limbs Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau Absence of identified alternative diagnosis for weakness Clinical case definitions for diagnosis of Miller Fisher syndrome Level 1 of diagnostic certainty Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes, and ataxia Abbreviation: CSF, cerebrospinal fluid. Absence of limb weakness


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InternalMed_Harrison. Level 1 of diagnostic certainty Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes, and ataxia Abbreviation: CSF, cerebrospinal fluid. Absence of limb weakness Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau Cytoalbuminologic dissociation (i.e., elevation of cerebrospinal protein above the laboratory normal and total CSF white cell count <50 cells/μL) Nerve conduction studies are normal, OR indicate involvement of sensory nerves only Absence of identified alternative diagnosis Level 2 of diagnostic certainty Absence of limb weakness Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau CSF with a total white cell count <50 cells/μL) (with or without CSF protein elevation above laboratory normal value) Nerve conduction studies are normal, OR indicate involvement of sensory nerves only


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InternalMed_Harrison. Nerve conduction studies are normal, OR indicate involvement of sensory nerves only Absence of identified alternative diagnosis Level 3 of diagnostic certainty Absence of limb weakness Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau Absence of identified alternative diagnosis Source: From JJ Sejvar et al: Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 29:599, 2011. Validation study published by C Fokke et al: Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain 137:33, 2014.


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InternalMed_Harrison. of intubation) of tracheotomy, and chest physiotherapy. As noted, ~30% of patients with GBS require ventilatory assistance, sometimes for prolonged periods of time (several weeks or longer). Frequent turning and assiduous skin care are important, as are daily range-ofmotion exercises to avoid joint contractures and daily reassurance as to the generally good outlook for recovery.


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InternalMed_Harrison. Prognosis and Recovery Approximately 85% of patients with GBS achieve a full functional recovery within several months to a year, although minor findings on examination (such as areflexia) may persist and patients often complain of continued symptoms, including fatigue. The mortality rate is <5% in optimal settings; death usually results from secondary pulmonary complications. The outlook is worst in patients with severe proximal motor and sensory axonal damage. Such axonal damage may be either primary or secondary in nature (see “Pathophysiology,” above), but in either case successful regeneration cannot occur. Other factors that worsen the outlook for recovery are advanced age, a fulminant or severe attack, and a delay in the onset of treatment. Between 5 and 10% of patients with typical GBS have one or more late relapses; such cases are then classified as chronic inflammatory demyelinating polyneuropathy (CIDP).


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InternalMed_Harrison. CIDP is distinguished from GBS by its chronic course. In other respects, this neuropathy shares many features with the common demyelinating form of GBS, including elevated CSF protein levels and the Edx findings of acquired demyelination. Most cases occur in adults, and males are affected slightly more often than females. The incidence of CIDP is lower than that of GBS, but due to the protracted course, the prevalence is greater.


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InternalMed_Harrison. Clinical Manifestations Onset is usually gradual over a few months or longer, but in a few cases, the initial attack is indistinguishable from that of GBS. An acute-onset form of CIDP should be considered when GBS deteriorates >9 weeks after onset or relapses at least three times. Symptoms are both motor and sensory in most cases. Weakness of the limbs is usually symmetric but can be strikingly asymmetric in multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy variant (Lewis-Sumner syndrome) in which discrete peripheral nerves are involved. There is considerable variability from case to case. Some patients experience a chronic progressive course, whereas others, usually younger patients, have a relapsing and remitting course. Some have only motor findings, and a small proportion present with a relatively pure syndrome of sensory ataxia. Tremor occurs in ~10% and may become more prominent during periods of subacute worsening or improvement. A small proportion have


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InternalMed_Harrison. proportion present with a relatively pure syndrome of sensory ataxia. Tremor occurs in ~10% and may become more prominent during periods of subacute worsening or improvement. A small proportion have cranial nerve findings, including external ophthalmoplegia. CIDP tends to ameliorate over time with treatment; the result is that many years after onset, nearly 75% of patients have reasonable functional status. Death from CIDP is uncommon.


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InternalMed_Harrison. Diagnosis The diagnosis rests on characteristic clinical, CSF, and electrophysiologic findings. The CSF is usually acellular with an elevated protein level, sometimes several times normal. As with GBS, a CSF pleocytosis should lead to the consideration of HIV infection, leukemia or lymphoma, and neurosarcoidosis. Edx findings reveal variable degrees of conduction slowing, prolonged distal latencies, distal and temporal dispersion of CMAPs, and conduction block as the principal features. In particular, the presence of conduction block is a certain sign of an acquired demyelinating process. Evidence of axonal loss, presumably secondary to demyelination, is present in >50% of patients. Serum protein electrophoresis with immunofixation is indicated to search for monoclonal gammopathy and associated conditions (see “Monoclonal Gammopathy of Undetermined Significance,” below). In all patients with presumptive CIDP, it is also reasonable to exclude vasculitis, collagen vascular disease