Acquired Polyneuropathies

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72 Acquired Polyneuropathies

Ted M. Burns, Michelle Mauermann, Jayashri Srinivasan

Diagnostic Approach

Clinical Vignette

A 51-year-old woman complained of acute onset of right hand weakness and pain for 2 weeks and acute onset of painful left foot drop for 3 days. She describes the pain as being “burning and aching” and associated with some prickling and “pins and needles” sensation. Over the past month she has also experienced low-grade fevers, fatigue, malaise, and an unexplained 15-pound weight loss. Her past medical history is only remarkable for adult-onset asthma, for which she uses an inhaler as needed. She is on no other medications. The family history is unremarkable. She does not smoke or drink alcohol. Review of systems is otherwise negative, including for any symptoms of autonomic nervous system dysfunction.

Her examination was noteworthy for marked weakness and sensory loss in the right ulnar nerve and left peroneal nerve distributions; there was also sensory loss over the lateral aspects of the left foot. Nerve conduction studies (NCS) and needle electromyography (EMG) confirmed moderate to severe right ulnar, left peroneal, and left sural mononeuropathies. NCS/EMG demonstrated relatively recent-onset, prominent axonal damage without any findings of prominent demyelination.

Laboratory testing was remarkable for a very elevated erythrocyte sedimentation rate of 82 mm/hour (nonspecific indicator of systemic inflammation). Hypereosinophilia was present on the complete blood count (CBC). A left sural nerve biopsy was performed confirming the clinical suspicion of vasculitic neuropathy. She was diagnosed with Churg–Strauss syndrome with vasculitic neuropathy and was started on high-dose corticosteroids. This led to gradual resolution of her symptoms; 18 months later, there were only minimal residual deficits in the involved peripheral nerves.

The evaluation for the etiology of a patient’s polyneuropathy can be very challenging for many reasons, including the fact that there are more than 100 potential etiologies (Fig. 72-1). Ultimately the polyneuropathy is determined to be acquired (i.e., caused by some other disease or exposure) in one third of cases (Box 72-1), inherited in another one third of cases (see Chapter 71), and—in spite of appropriate testing—idiopathic in the remaining one third of cases. In order to focus on a smaller list of potential etiologies so that the evaluation can be simplified, we believe that it is best for the clinician to first characterize the polyneuropathy and the patient. We will present one method for characterizing neuropathy that is easy to remember, based on four simple clinical questions about the neuropathy and the patient: “What?” “Where?” “When?” and “What setting?”

Figure 72-1 Peripheral Neuropathies: Clinical Manifestations.

“What?” refers to what nerve fiber modalities (motor, sensory, autonomic, or a combination) are involved? The identification of sensory nerve involvement, at a minimum, allows the clinician to exclude other neuromuscular diseases not associated with sensory dysfunction, such as disorders of anterior horn cells (e.g., amyotrophic lateral sclerosis), neuromuscular transmission (e.g., myasthenia gravis), or of muscle (myopathy). When sensory symptoms and signs are present, it is useful to characterize neuropathic sensory symptoms into “positive” or “negative” because acquired neuropathies are usually accompanied by positive neuropathic sensory symptoms and inherited neuropathies are usually not. Positive sensory symptoms may be painful (e.g., “burning,” “freezing,” or “throbbing”) or painless (e.g., “tingling” or “swelling”) (Box 72-2). Paresthesias and pain (positive neuropathic sensory symptoms) are common complaints for patients with diabetic, vasculitic, alcoholic, or uremic neuropathy and patients with Guillain–Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In the clinical vignette presented above, the patient had prominent positive neuropathic sensory symptoms, strongly suggesting that the etiology of her neuropathy is acquired rather than inherited. Patients with neuropathy often also complain of exaggerated discomfort to painful sensory stimuli (hyperalgesia) and to nonpainful sensory stimuli (allodynia). Patient complaints indicative of negative neuropathic sensory symptoms include loss of sensation and imbalance (i.e., sensory ataxia). Most patients with neuropathy have some degree of motor nerve involvement that at times is overshadowed by the sensory complaints. Our patient had prominent motor nerve fiber involvement.

Identification of autonomic nerve involvement can be an important clue because only a small number of neuropathic processes affect both autonomic and somatic nerves (e.g., GBS, paraneoplastic neuropathy, diabetic neuropathy, amyloid neuropathy) (Box 72-3). Autonomic symptoms include lightheadedness, syncope, diarrhea, constipation, postprandial bloating, early satiety, urinary complaints, erectile dysfunction, abnormal or absent sweating, and dry mouth and eyes (Fig. 72-2). Our patient did not have discernible autonomic nervous system involvement.

Figure 72-2 Dysautonomia with Polyneuropathies.

“Where?” refers to the distribution of nerve damage. An important diagnostic watershed is the determination of whether the process is “length dependent” (e.g., distal) or not. Length-dependent neuropathies manifest first in the feet and are symmetric. Non–length-dependent neuropathies are not necessarily evident initially in the feet and may be asymmetric, focal, or multifocal. The etiology of length-dependent neuropathies is usually inherited, metabolic/toxic, or idiopathic whereas a neuropathy that is not length dependent is often caused by an immune-mediated or infectious process.

Our vignette patient clearly had a neuropathy that was not length-dependent (it was multifocal). Some examples of non–length-dependent neuropathies are polyradiculoneuropathies (e.g., GBS), plexopathies (often inflammatory), sensory ganglionopathy (e.g., paraneoplastic subacute sensory neuronopathy caused by small cell lung cancer), and multifocal mononeuropathies (e.g., mononeuritis multiplex caused by vasculitis). Our patient’s presentation was of painful multifocal mononeuropathies, which is typical of mononeuritis multiplex caused by vasculitis.

“When?” refers to the temporal evolution of the neuropathy. Because of confusion over what is meant by “acute,” “subacute,” and “chronic,” it is often best to describe symptom onset based on whether or not the neuropathic symptoms had a compelling, definite date of onset. A definite date of symptom onset almost always indicates an acute or subacute onset typical of an immune-mediated or infectious etiology. A less-exact date of onset suggests a gradual or insidious onset, indicative of inherited, idiopathic, or toxic/metabolic etiologies. The pace of progression following symptom onset is also an important consideration. Symptom onset and pace of progression often correlate in a predictable manner, owing largely to the underlying mechanism. Mononeuritis multiplex caused by systemic vasculitis, which is at the top of the differential diagnosis for our vignette patient, typically presents with a series of painful mononeuropathies of acute onset, occurring one after the other with the rapid development of significant morbidity. Our patient’s description of acute-onset mononeuropathies is typical of mononeuritis multiplex.

“What setting?” refers to an elaboration of the unique clinical circumstance of the individual patient. This is done by determining what in the patient’s past medical history, medication list, social history, family history, and the review of systems may be relevant (Fig. 72-3). An understanding of the significance of these clinical factors requires knowledge of the risk factors of neuropathy and knowledge of the clinical features of the diseases that may be risk factors for neuropathy. For example, unexplained weight loss raises concern for vasculitis or malignancy (e.g., small cell lung cancer), both of which cause an immune-mediated neuropathy. The neuropathy secondary to malignancy (e.g., paraneoplastic neuropathy) usually presents differently than vasculitic neuropathy, so it is usually not too difficult to differentiate these two etiologies. A clinical setting of known diabetes mellitus or known kidney disease would elevate those comorbidities on the differential diagnosis. Heavy metal poisoning or other intoxication, although rare, needs to be considered in the patient with systemic symptoms (e.g., nausea, vomiting) and other manifestations suspicious for poisoning (Fig. 72-4). Our patient’s presentation is of vasculitic neuropathy rather than paraneoplastic neuropathy.

Figure 72-3 Peripheral Neuropathies: Metabolic, Toxic, and Nutritional Etiology.

Figure 72-4 Peripheral Neuropathy Caused by Heavy Metal Poisoning.

The fifth step in characterization requires NCS and EMG. NCS and EMG can contribute to (or rarely refute) the clinical characterization in terms of “what” and “where,” as well as provide another view of the temporal evolution (“when”). NCS and EMG can also characterize the neuropathy as being primarily axonal or demyelinating. Neuropathies with axonal injury are far more common than those primarily with demyelination, but the identification of a primarily demyelinating polyneuropathy is very important because acquired demyelinating polyneuropathies (e.g., GBS, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy) are generally treatable. They are usually immune-mediated and treatable with immunotherapy (e.g., corticosteroids, intravenous immunoglobulin [IVIG], plasmapheresis) (Box 72-4). NCS and EMG can also assess for subclinical involvement and provide baseline parameters in case future testing is necessary to monitor the patient’s course. Our patient’s NCS and EMG confirmed multiple, axonal mononeuropathies. It is important to note that the localization of each mononeuropathy was not at common sites of nerve entrapment, such as the elbow for the ulnar nerve and the fibular head for the peroneal nerve; thus, a compression or entrapment mechanism of injury is not plausible (given the other facts of the case, it would have been very unlikely anyway).

Vasculitis is only one of the more than 100 different causes of neuropathy (Fig. 72-5). It is a far less common cause of acquired neuropathy than diabetic, alcoholic, or uremic neuropathy, but it is very important to diagnose—and to do so quickly—because undiagnosed and untreated systemic vasculitis may be fatal. See discussion on vasculitic neuropathies below.

Figure 72-5 Mononeuritis Multiplex due to Systemic Vasculitis.

Clinical Vignette

A 72-year-old man reported a 4-year history of numb feet characterized as a feeling of “cotton between the toes.” Walking on bare feet became uncomfortable. The numbness ascended circumferentially to his ankles. He no longer trusted his balance to put on his pants without support. Difficulty wiggling the toes was the only indication of weakness. He had no symptoms in his hands or face, indications of dysautonomia, or systemic illness. His medications included a diuretic and a multivitamin. He had no toxic exposure or affected family members. The patient appeared well and had bilateral hammertoe deformities. Neurologic findings included an inability to spread his toes and intrinsic foot muscle atrophy. Muscle stretch reflexes were normal in the arms, diminished at the knees, and absent at the ankles. There was a distal maximal graded stocking distribution sensory loss to light touch, pinprick, temperature, vibration, and proprioception to mid calf bilaterally. He wobbled slightly on Romberg testing but did not fall.

EMG demonstrated a length-dependent, primarily axonal, sensorimotor polyneuropathy. An undefined hereditary sensory neuropathy could not be excluded, although his children were examined clinically and electrodiagnostically. Laboratory investigation did not demonstrate an etiologic mechanism. Nerve biopsy was not indicated.

The symmetric pattern of sensory and reflex loss and the subtle distal motor involvement supported the length-dependent nature of his neuropathy. Although his hammertoes were compatible with a hereditary neuropathy, positive sensory symptoms, his age, and the absence of affected family members made Charcot–Marie–Tooth disease (CMT) an unlikely consideration. Distal sensory symptoms could occur with myelopathies; however, the characteristic distribution of clinical findings and absence of urinary sphincter problems was consistent with a length-dependent polyneuropathy (LDPN). Annual follow-up revealed minimal progression of his neuropathy.

Idiopathic Length-Dependent Polyneuropathies

Polyneuropathies are one of the most common neurologic disorders; the length-dependent pattern is the most prevalent. Although there are many recognized causes of polyneuropathy, specific mechanisms have not been identified in 30–40% of patients, and these patients are deemed to have idiopathic neuropathy (Box 72-5).

Box 72-5 Length-Dependent Polyneuropathies

CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMT, Charcot–Marie–Tooth neuropathy; GBS, Guillain–Barré syndrome; HNPP, hereditary neuropathy with liability to pressure palsy; LDPN, length-dependent polyneuropathy; MM, mononeuritis multiplex; MMN, multifocal motor neuropathy; PNSS, positive neuropathic sensory symptoms; SN, sensory neuropathy.

Hereditary

Charcot–Marie–Tooth disease

Hereditary sensory neuropathy (HSN or HSAN)

Idiopathic

Amyloidosis

Mitochondrial disorders

Idiopathic

Cryptogenic sensory or sensorimotor polyneuropathy

Dysimmune/Inflammatory

Amyloidosis

Monoclonal gammopathy of unknown significance

Sjögren syndrome (LDPN most common phenotype, may associate with SN, trigeminal neuropathy)

Rheumatoid arthritis

Sarcoidosis (LDPN most common phenotype, may produce MM, cranial neuropathy, usually occurs in established disease)

Vasculitis (25–30% of neuropathy cases present as LDPN, may be presenting manifestation, MM more typical)

Infectious

HIV

Lyme disease

Malnutrition

B-vitamin deficiency (B₁₂, thiamine)

Metabolic

Critical illness polyneuropathy

Diabetes mellitus and impaired glucose tolerance

Gluten-sensitive enteropathy

Hypothyroidism

Uremia

Peripheral nerve axons are fine-caliber distal portions of long individual cells, sometimes longer than 1 m. They depend on their cell bodies, within dorsal root ganglia or anterior horns, and their axonal transport mechanisms for nutrition and other factors for maintenance of homeostasis. Length-dependent patterns of dysfunction are thought to relate to impaired cell body metabolism or axonal transport within the nerves’ most vulnerable components. As the neuropathy progresses, the fingers typically become symptomatic when lower extremity symptoms have ascended to approximately the mid-shin to knee level. Very rarely in advanced cases, the chin, nose, and midline trunk are involved.

Typical patients with primary sensory LDPN note tingling, numb, or burning sensations, often pronounced at rest, particularly at night. Occasionally, exercise exacerbates these unpleasant sensations. When weakness is present, foot and toe extensors and foot evertors are more affected than plantar flexors. Gait is compromised because of weakness, or painful dysesthesia. Muscle stretch reflexes are variably affected but commonly ankle jerks are diminished.

Motor-predominant LDPNs have a limited number of etiologies. These are primarily genetically determined (i.e., CMT) or, less commonly, immunologically acquired, multifocal motor neuropathies. More common motor disorders related to diseases affecting the motor neuron (anterior horn cell), neuromuscular junction, or skeletal muscle base usually have asymmetric or generalized patterns of involvement.

Pure sensory neuropathies fit into the LDPN pattern such as with diabetes mellitus, renal disease, vitamin deficiencies, various toxins, Sjögren syndrome, and amyloidosis (Fig. 72-6), or represent a primary sensory ganglionopathy. The latter may be clinically suspected by its initially proximal, non–length-dependent pattern of involvement. EMG can aid confirmation.

Figure 72-6 Amyloid Neuropathy.

Overt dysautonomia features accompanying a peripheral neuropathy are uncommon. When present, they suggest limited etiologies, including diabetes mellitus, paraneoplastic disorder, amyloidosis, and rare hereditary processes.

Dissociation of separate sensory modalities may lend valuable clues. A small-fiber sensory neuropathy is suggested by burning in the feet of patients with impaired pain and thermal sensation and sparing of vibration and proprioceptive sense. Many demonstrate marked distal hyperpathia to touch or stocking sensory loss. Most small fiber neuropathies do not have identifiable etiologic mechanisms.

Identifying the LDPN per se is usually the easiest part of the evaluation. Determination of etiologic mechanism requires careful consideration and thorough investigation, although this does not always yield precisely identifiable mechanisms. For example, not all neuropathies in patients with diabetes mellitus are related to that disorder. Other mechanisms may be responsible and must be sought. After determining that a neuropathy best fits an LDPN pattern, the clinician must search for additional clues to the differential diagnosis. Evaluation of a patient’s risk factor profile from personal and family history, toxic exposures, and other symptoms such as pain, dysautonomia, or indications of a systemic disorder is important. A careful evaluation leads to specific diagnosis in about 50% of patients. Diagnosis is often made on an associative basis without absolute proof of causation. Treatable neuropathies are more common among disorders presenting acutely or subacutely. Toxic or metabolic etiologies (see Fig. 72-3) are common causes of sensory LDPN, whereas genetic mechanisms underlie most motor-predominant distal polyneuropathies.

Idiopathic polyneuropathies are of uncertain etiology. No specific cause for the neuropathy can be determined despite laboratory evaluations. Diabetic neuropathies and neuropathies associated with glucose intolerance are usually excluded from this category. Electrodiagnostic studies will confirm an axonal sensory predominant process. These neuropathies are usually slowly progressive.

Careful clinical evaluation is important, particularly with a history of familial disorder. A negative family history is insufficient to exclude a hereditary diagnosis. Clinical examination, brief electrodiagnostic testing, and DNA mutational analyses of first-degree family members commonly uncover unrecognized affected individuals.

Forthright history taking in reference to medications, addictions (including alcohol and tobacco), intravenous (IV) drugs with predilection for hepatitis C and cryoglobulinemia, and occupational or environmental exposure such as glue sniffing or the classic bull’s-eye rash of Lyme disease can point to a specific LDPN diagnosis. A thorough physical examination may suggest signs of CMT with pes cavus, Sjögren syndrome with dry eyes and mouth, arsenic poisoning with Mees lines, Raynaud phenomena and purpuric skin eruptions with cryoglobulinemia, pinch purpura with amyloidosis, angiokeratoma in the groin with Fabry disease, and enlarged yellow-orange tonsils of Tangier disease. Exploring these historic and physical findings can often prevent undirected selection of diagnostic tests. Individualized investigations for each clinical circumstance are encouraged to avoid the risk of providing a false conclusion, often at considerable expense.

Electrodiagnostic testing is indicated to confirm the presence of a large fiber neuropathy, to assess the pattern and severity of the neuropathy, and to distinguish demyelinating from axonal processes. Abnormal EMG findings are difficult to define with small fiber neuropathies because nerve conduction studies only test the larger proprioceptive fibers and not the small pain fibers affected in these disorders. Therefore, normal findings do not preclude the existence of small fiber neuropathies. Autonomic nervous system testing, quantitative sensory testing, and skin biopsy may be required for diagnostic support. Sural nerve or abdominal fat pad biopsy may be helpful for patients with LDPN with suspected amyloidosis, particularly those with orthostatic hypotension, where amyloidosis is more likely.

Acquired metabolic disorders are common causes of LDPN. Diabetes mellitus may produce a number of neuropathic phenotypes, most commonly an LDPN sensory-predominant painful phenotype. Typically, it occurs with long-standing diabetes, but a small-fiber neuropathy may be the presenting feature of impaired glucose tolerance.

Many potential peripheral neurotoxins exist, including alcohol and therapeutic drugs. In some pharmaceuticals, neurotoxicity limits the dose. Neuropathies resulting from cryptic sources such as heavy metals are uncommon or uncommonly recognized (see Fig. 72-4). However, in certain parts of North America arsenic poisoning is still seen. The role of nutritional and vitamin deficiency versus that of ethanol in the development of “alcoholic” neuropathy is uncertain.

Immune-mediated neuropathies are associated with monoclonal proteins, antibodies, or both directed against peripheral nerve constituents. Monoclonal proteins occur more commonly in patients with polyneuropathy than in age-matched controls without neuropathy. However, a precise cause-and-effect relationship is unproven. The strongest association occurs with IgM-K monoclonal proteins, with or without presence of associated antimyelin-associated glycoprotein (MAG) antibodies.

Infectious causes of LDPN are less common; HIV is an exception. Distal symmetric and often painful polyneuropathies are most commonly associated with HIV infection. Usually associated with low CD4 counts, in advanced disease, they may be complicated by neuropathies associated with antiretroviral drug treatments. Lyme disease may cause an LDPN pattern but this is uncommon compared with the polyradiculoneuropathy or mononeuritis multiplex pattern.

Treatment

Specific therapies are sometimes available when the etiology can be identified, but this is achieved in a frustratingly modest percentage of cases. Stabilization or reversal of neuropathy, or both, can occur with successful treatment of uremia, nutritional deficiencies, and hypothyroidism. Removing neurotoxic drugs may completely reverse mild neuropathies or curtail further progression in more severe cases. A therapeutic trial of prednisone, IVIG, or plasmapheresis may have striking results for patients with an immune-mediated etiology. Unfortunately, some patients with LDPN respond poorly to treatment. In the absence of a definite diagnosis known to respond to immunomodulating agents, it is prudent to curtail treatment if no significant response occurs in a therapeutic trial of 3–4 months. Patients, particularly those with decreased pain and thermal perception such as occurs in hereditary sensory neuropathies, need to understand the importance of diligent foot care to prevent secondary infectious complications of unrecognized wounds, particularly osteomyelitis.

The underlying causes of neuropathies determine the prognosis. Idiopathic neuropathies usually progress slowly over years and are infrequently disabling. In particular, most of these LDPNs rarely lead to need for ambulatory support, that is, a wheelchair. Often the physician needs to specifically discuss this with the patient and his or her family as frequently the patient is too frightened to ask. This time taken for discussion is very reassuring to patients in whom no cause is found.

Neuropathies Associated With Diabetes

Diabetes is the most common metabolic disorder associated with neuropathy. Diabetes causes neuropathy in approximately 30–50% of patients and is seen in patients with poor glycemic control. Diabetes can cause various types of neuropathy including distal symmetric sensory predominant neuropathy, polyradiculoneuropathy, autonomic neuropathy, cranial neuropathies, and compressive neuropathies such as carpal tunnel syndrome, ulnar neuropathy, and meralgia paresthetica.

The sensory predominant LDPN associated with diabetes is the most common type of neuropathy seen. Sensory loss begins in the tips of the toes and gradually progresses to involve the fingers. This may be associated with degeneration of small nerve fibers and can be very painful. Additionally the LDPN of the patient with diabetes may coexist with a diabetic vasculopathy. This combination can result in nonhealing ulcers and rarely gangrene of the toes requiring surgery such as amputations (Fig. 72-7). Motor strength is usually preserved and electrodiagnostic studies will reveal a length-dependent sensory predominant axonal process. Treatment of this condition consists of improved control of diabetes and symptomatic treatment of neuropathic pain. Medications such as gabapentin, pregabalin, and tricyclic antidepressants are used for neuropathic pain.

Figure 72-7 Neuropathic Foot (Charcot Neuropathy).

Diabetic polyradiculoneuropathy (Bruns–Garland syndrome) is an asymmetric painful condition seen in patients with poor diabetic control. Lumbar involvement presents with severe pain in the legs; clinical examination will demonstrate significant asymmetric proximal greater than distal weakness of the lower extremities. Diabetic polyradiculoneuropathy can also involve the thoracic dermatomes, resulting in severe abdominal or thoracic pain. Nerve conduction studies will reveal findings suggestive of lumbar root, plexus, and peripheral nerve involvement. Nerve biopsies may reveal perivascular inflammatory infiltrates and findings of ischemic injury, suggesting that the pathogenesis may be immune mediated. Immune-modifying treatments such as IVIG or prednisone may be beneficial.

Diabetic autonomic neuropathies present with pupillary (Argyll Robertson pupil), sweat, gastrointestinal (gastroparesis, diarrhea), urologic (erectile dysfunction), and cardiovascular (orthostatic hypotension, bradycardia) dysfunction.

Cranial neuropathies such as pupil-sparing third nerve palsy or facial palsy may be associated with diabetes. The incidence of compressive neuropathies is also significantly higher in diabetic patients.

Cobalamin Deficiency

Cobalamin (vitamin B₁₂) deficiency frequently occurs in people older than age 60. The most common etiology is pernicious anemia, an autoimmune disease that leads to impaired absorption of cobalamin due to the absence of intrinsic factor in the setting of atrophic gastritis. Other causes include dietary avoidance (vegetarians), gastrectomy, gastric bypass surgery, and nitrous oxide abuse. The neuropathy associated with cobalamin deficiency can be similar to other toxic/metabolic etiologies in that there is distal numbness and positive neuropathic sensory symptoms. However, many patients have a non–length-dependent presentation. These patients often present with sensory symptoms beginning in the hands, or simultaneously in the hands and feet. Commonly there is no pain. The neuropathy might begin suddenly, similar to other acquired neuropathies, rather than with a gradual insidious onset. This may occur immediately after surgery requiring general anesthesia wherein nitrous oxide was used for induction. This agent will cause a precipitous sensory polyneuropathy when the patient has very low cobalamin stores, something that may have previously been recognizable. The neuropathy often coexists with a myelopathy, which serves as a clue to the diagnosis but can also make it difficult to differentiate symptoms that are primarily attributable to the neuropathy rather than the myelopathy.

It is important to diagnose cobalamin deficiency as it is a treatable neuropathy. In order to make the diagnosis, the serum B₁₂ levels should be evaluated. If they are below normal range, replacement therapy should be initiated. In those patients with B₁₂ levels in the low normal range (less than 300 pg/mL), it is important to check the serum homocysteine and methylmalonic acid levels as these will be elevated in cobalamin-deficient patients. Another important clue to cobalamin deficiency is elevation of the mean corpuscular volume (MCV). Electrophysiological studies demonstrate an axonal neuropathy, and somatosensory evoked potentials and magnetic resonance imaging (MRI) may aid in demonstrating a coexisting myelopathy with involvement of the posterior columns. Cobalamin deficiency should be treated with vitamin B₁₂ replacement therapy. The route of therapy (intramuscular vs. oral) and duration of therapy depends on the underlying cause and severity of the deficiency.

Guillain–Barré Syndrome

Clinical Vignette

A 47-year-old man reported a 10-day history of progressive distal and proximal weakness and paresthesias in his arms and legs. He did not report bowel or bladder dysfunction, dysarthria, dysphagia, or dyspnea. He remembered a mild and transient upper respiratory infection 2 weeks before onset of his neuropathic symptoms but otherwise had been well. His medical, family, and social history were unremarkable. He was not taking medications.

Vital signs were normal without orthostatic hypotension or tachycardia. Forced vital capacity and negative inspiratory force were normal. Neurologic examination demonstrated mild facial and symmetric primarily distal weakness in the lower and upper extremities. The patient was areflexic, and his toes were flexor to plantar stimulation. Vibration and joint position sensation were abnormal at the toes and ankles but normal at the fingers. Pinprick, temperature, and light touch sensation were normal, with no spinal cord “sensory level.” The patient displayed mild dysmetria with heel-to-shin testing but performed well on finger-to-nose testing. His gait was characterized by weakness, with bilateral foot drop, and he was unsteady. The Romberg test was abnormal.

Cerebrospinal fluid (CSF) examination results demonstrated increased protein of 107 mg/dL and only 3 WBCs. EMG disclosed multifocal signs of demyelination. This clinical and laboratory set of findings was highly suggestive of GBS. The significant degree of weakness made him a good candidate for immunomodulatory therapy. Plasmapheresis (PE) was begun on the second hospital day, with IVIG held in reserve. His autonomic and respiratory statuses were monitored closely. Except for mild intermittent tachycardia, the patient remained free of dysautonomia or respiratory compromise. By day 9 of hospitalization, the patient was walking without assistance. He was transferred to a rehabilitation unit after completing the PE. At follow-up 4 weeks later, he was asymptomatic.

The patient’s rapidly evolving polyneuropathy affected motor and sensory function in a non–length-dependent fashion. Presentation with generalized areflexia, concomitant with antecedent respiratory infection, was typical of GBS. Subsequent electrodiagnostic and CSF examination results confirmed this diagnosis.

Guillain–Barré syndrome is a classic acute autoimmune polyneuropathy (Fig. 72-8). Characteristically, it presents in a previously healthy person with the rapid onset of symmetric weakness, areflexia, and generally minimal sensory symptoms with the exception of severe pain in some individuals. Typical CSF findings are an albuminocytologic dissociation with increased protein and fewer than 5–10 WBCs. Additional findings include gait ataxia and cranial and autonomic nerve involvement. Although GBS is the most common cause of acute flaccid paralysis, a primary spinal cord lesion and rarely a poliomyelitis-like illness such as seen now with the West Nile virus, must always be considered early in the clinical course.

Figure 72-8 Guillain–Barré Syndrome: Pathogenesis and Clinical Manifestations.

Figure 72-8 Guillain–Barré Syndrome: Electrophysiologic Findings and Clinical Manifestations.

GBS, sometimes known as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are common acquired polyradiculopathies. Both are autoimmune processes that share the unusual feature of significant widespread peripheral—often including nerve root (Fig. 72-9) and sometimes cranial nerve—involvement. Consequently, these disorders are categorized as polyradiculoneuropathies rather than polyneuropathies.

Figure 72-9 Guillain–Barré.

The major clinical difference between GBS and CIDP is the temporal course. GBS is a monophasic illness of acute onset that usually reaches a nadir within 1–4 weeks and then gradually improves (see Fig. 72-8). CIDP has a slower onset and more prolonged course that is progressive, monophasic, or relapsing. Most cases of childhood or adult CIDP present within 6 months of symptom onset. Sometimes CIDP can present acutely, mimicking GBS, to be diagnosed correctly only later when a clinical relapse occurs.

The immune attack in GBS and CIDP is widespread and occurs proximally at the nerve roots and distally at the motor axon terminal. These two sites are theoretically more vulnerable because of their less complete blood–nerve barriers. Both cellular and humoral immune mechanisms seem to be involved. Lymphocytes and macrophages are the effector cells involved in damaging myelin and the adjacent axons (see Fig. 72-8). Motor, sensory, and autonomic nerves are affected. The weakness and sensory disturbances are due to nerve fiber action potential conduction block (secondary to demyelination) or conduction failure (due to axon damage).

The pathophysiology of GBS, and perhaps CIDP, relates to the immune system probably being first primed as it responds to foreign molecules, such as a virus or bacteria. Later, the immune system inappropriately attacks host tissue that shares homologous epitopes, for example, gangliosides found on the cell wall of certain bacteria and the peripheral nerve myelin of the host. This pathologic process has been termed molecular mimicry. In keeping with molecular mimicry, approximately two thirds of patients with GBS give a history of antecedent infection. Campylobacter jejuni and cytomegalovirus are the most frequent antecedent infections in GBS, usually as gastroenteritis or respiratory infection 1–4 weeks before the appearance of GBS symptoms. Antecedent infection is observed less commonly in CIDP.

The cardinal features of GBS and CIDP are predominantly symmetric motor symptoms with less consistent sensory symptoms affecting all limbs. Furthermore, the proximal involvement in GBS and CIDP, rather than the classic distal weakness of a polyneuropathy, aids the distinction of a polyradiculoneuropathy. Typically, in GBS and CIDP, motor symptoms overshadow sensory paresthesias such as “tingling” or “pins and needles.” These symptoms are more pronounced distally in a stocking-glove distribution. Back pain is common in GBS, particularly in children, but is not found in CIDP. At times, pure motor or pure sensory variants of GBS or CIDP occur but remain recognizable because of the frequently associated prodrome; the acute, symmetric, and generalized pattern of weakness; the areflexia; and the supportive information gained by electrodiagnostic and CSF examinations.

Gait difficulty often occurs early on in patients with polyradiculoneuropathies. It may manifest as trouble climbing stairs, arising from chairs, unsteadiness, falls, or difficulty with arm use. Facial weakness occurs in more than half of patients with GBS but is much less common in CIDP. Ophthalmoplegia, dysarthria, and dysphagia may occur in both disorders, more frequently in GBS.

Neurologic examination demonstrates prominent proximal and distal weakness, rarely slightly asymmetric. More subtle proximal and distal strength should be sought by having the patient rise from a chair, step up on a step, kneel on one knee and stand, walk on the heels, and walk on the toes. Reduced or absent muscle stretch reflexes are important early clinical clues that the symptoms are likely from a peripheral nerve disorder. However, retention of reflexes may occur in early GBS and occasionally in CIDP. There is an associated mild distal sensory impairment in the feet.

Respiratory compromise occurs in 15–30% of patients with GBS. Endotracheal intubation for airway protection and mechanical ventilation for diaphragmatic weakness are necessary. Airway and respiratory compromise are rare in CIDP.

The autonomic nervous system is frequently involved in GBS, especially in severe cases. Dysautonomia in GBS commonly manifests as sinus tachycardia but may result in other cardiac arrhythmias or labile blood pressures that may be life threatening and warrant close observation. Urinary retention, adynamic ileus, and constipation sometimes occur. Overt dysautonomia in CIDP is rare.

Differential Diagnosis Of Demyelinating Polyneuropathies

Subjective sensory symptoms have differential diagnostic importance favoring GBS or CIDP over other motor unit disorders, including myopathies, neuromuscular transmission disorders, or motor neuron disorders. However, the possibility of acute spinal cord lesion or other fulminating forms of polyneuropathy should always be considered.

Because sensory symptoms also occur with myelopathies, the possibility of an acute or subacute myelopathy with evolving spinal cord compression that may necessitate emergent intervention must always be considered, especially early in the patient’s clinical course. Important clues to the possibility of a myelopathy include the preservation or hyperactivity of muscle stretch reflexes, Babinski signs, a cord level on careful sensory testing and sphincter dysfunction. Patients presenting with a polyradiculoneuropathy do not have a spinal cord sensory level, and preservation of muscle stretch reflexes is unusual in GBS and CIDP, although such may occasionally occur for ≥48 hours.

Transverse myelitis (TM) is the most common acute spinal cord lesion leading to confusion in the differential diagnosis of GBS. Criteria for diagnosis of TM include paraparesis, a well-defined sensory level, severe bladder dysfunction, and myelitic findings on MRI. Often motor and sensory symptoms present equally but motor findings may predominate. Sphincter control is lost in most patients with TM. It may be difficult to make a clinical differential between GBS and TM in some individuals without spinal cord MRI. Although urinary retention and constipation occasionally occur in GBS for the first day, these symptoms are very suggestive of a myelopathy, a conus medullaris, and/or cauda equina disorders. And when present in GBS, these symptoms are always very short-lived, usually clearing in a day or so. Thus, whenever sphincter difficulties persist in a patient with a GBS-like presentation, it is most likely that there is another pathophysiologic mechanism present within the spinal cord. Back pain is common in GBS but not in CIDP. However, when it has a radicular quality, particularly in the thoracic distribution, a thoracic spinal mass lesion, dural AVM, or TM must be considered.

The temporal course is of primary importance for differentiating GBS and CIDP from many other peripheral neuropathies. Patients with GBS and CIDP can usually give a specific date of symptom onset. This contrasts with many other acquired or inherited polyneuropathies wherein the onset is so insidious that the patient has no recall as to its precise timing.

Patients with mononeuritis multiplex (MNM) usually have an associated systemic or primary peripheral nervous system vasculitis. The precise temporal profile of the patient’s clinical symptomatology, that is, stepwise and asymmetric, is the primary diagnostic clue, in direct contrast to CIDP, which has a symmetric evolution. Typically MNM patients have sudden acute mononeuropathies, often affecting 4–6 specific nerves, particularly the peroneal, median, and ulnar, within a 2- to 6-week time period. For example, they may develop an acute foot drop from an acute vasculitis to the vasa nervorum of the peroneal nerve, and then within a matter of days acute sensory or motor loss in the distribution of another specific peripheral nerve such as the median or ulnar with numbness in the specific fingers supplied by these nerves. Subsequently if many nerves become involved, the clinical picture can mimic a symmetric generalized polyneuropathy. An increased erythrocyte sedimentation rate, often in the range of 60–100 mm/hour and a peripheral nerve biopsy demonstrating vasculitis provide important diagnostic information. Immediate high-dose immunosuppressive therapy, such as 60–100 mg prednisone daily, is indicated.

In tick paralysis, an unidentified tick saliva toxin most likely interacts with nerve ion channels, producing an acute paralytic illness mimicking GBS. This is most common in girls and young women, in whom ticks can become hidden in their scalp hair. Examiners must always search for ticks in any patient with an acute flaccid paralysis. These are relatively large sized when engorged and easily recognized (Fig. 72-10) when one carefully examines the scalp. In North America, the recovery is rapid and complete after the tick is dislodged.

Figure 72-10 Tick Embedded in Scalp Causing Tick Paralysis.

(Courtesy Dr. Thomas Swift.)

A number of toxins, including marine origin (red tide, ciguatoxin), metals (arsenic), solvents (hexacarbons), insecticides (organophosphates), and native plants such as Buckthorn, may produce acute generalized neuropathy. GBS may be the presenting sign of HIV before AIDS is definitively diagnosed. The findings of a disparate CSF examination with an inordinate pleocytosis are clues to search for CD4 cell count deficiencies and other clinical and laboratory signs of AIDS. Paralytic polio is preceded by a prodrome that includes back pain similar to GBS. Its multifocal and asymmetric pattern, the absence of sensory signs or symptoms, and CSF pleocytosis are distinguishing features. EMG demonstrates axon loss confined to motor nerves, consistent with anterior horn cell localization. Diphtheria is no longer of concern in industrialized nations, with the exception of parents who withhold immunization from their children. However, it still occurs in less fortunate economic settings. Acute intermittent and variegate porphyria may produce an acute generalized sensorimotor neuropathy mimicking GBS. Previous attacks, a family history of similar disorders, concomitant abdominal pain, and mental status changes are clinical clues that typify this rare biochemical disorder. An axonal character defined by EMG, rather than the typical demyelinating neuropathy of GBS, raises the possibility of porphyria.

Botulism and myasthenia gravis may produce an acute generalized weakness. Botulism is typically acute in onset and myasthenia is usually more indolent, although myasthenia gravis can have a relatively rapid presentation with cranial nerve and peripheral distribution weakness. Neither produces sensory system involvement. Both have a predilection for oculobulbar musculature. Botulism may also have prominent manifestations of cholinergic dysautonomia. EMG may be required for distinction from GBS. Lambert–Eaton myasthenic syndrome (LEMS) may mimic CIDP with a subacute onset of proximal weakness and areflexia. History of tobacco addiction and a dry mouth suggest LEMS (Chapter 74).

Severe hypokalemia and hypophosphatemia may produce weakness on an acute, generalized basis. Weakness severe enough to mimic GBS does not usually occur until potassium decreases to less than 2 mEq/mL and phosphate decreases to less than 1 mg/mL. Both typically occur in clinical contexts where severe hypokalemia or hypophosphatemia could be anticipated. Hypokalemia weakness is thought to be myopathic and is unassociated with sensory changes. Hyperkalemia with acute severe generalized weakness may also mimic GBS. Addison disease becomes an important diagnostic consideration. Barium carbonate poisoning, severe vomiting and diarrhea, and clay ingestions have also presented with similar clinical pictures. Sensory symptoms and signs in hypophosphatemia resemble GBS more closely than hypokalemic and hyperkalemic states.

AIDP and CIDP Variants

There are several recognized variants of GBS. There are acute axonal forms of GBS, which represents 5–10% of cases of GBS in North America but is more common in Japan and China. Acute motor axonal neuropathy (AMAN) tends to affect mostly children and large epidemics are seen in northern China during the summer. The onset of weakness is abrupt and is often preceded a few weeks by an upper respiratory or other infection. There are no sensory symptoms or signs. The CSF demonstrates albuminocytologic dissociation. The recovery usually begins within 3 weeks and is often complete. Acute motor and sensory axonal neuropathy (AMSAN) presents in adults and can affect any geographic location and occur during any season. There is involvement of sensory nerves and the course is often more protracted with severe residual disability. The most recognized variant is Miller Fisher syndrome (MFS). MFS usually follows an infection, such as Campylobacter jejuni. MFS presents with external ophthalmoplegia, ataxia, and areflexia, although all of these components need not be present. Facial weakness and dysarthria are particularly common in MFS. Many patients often have “overlapping GBS” with flaccid quadriparesis. Anti-GQ1b antibodies are present in approximately 95% of patients with acute MFS.

Chronic inflammatory demyelinating polyradiculoneuropathy associated with an IgG or IgA monoclonal gammopathy of undetermined significance usually presents clinically like CIDP, without a monoclonal protein, and treatment response is similar. However, an IgG-λ or IgA-λ (lambda) monoclonal gammopathy suggests the possibility of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes, particularly hyperpigmentation). Often an osteosclerotic or osteolytic bony lesion can be identified by performing a “metastatic bone” standard radiograph survey. Focused beam radiation therapy to these tumors can dramatically improve all POEMS syndrome aspects.

In contrast, an acquired demyelinating polyneuropathy associated with an IgM monoclonal protein frequently presents with more predominant sensory symptoms and signs, including sensory ataxia. It is less responsive to standard CIDP treatments. Many patients with a demyelinating polyneuropathy with an IgM monoclonal protein have high titers of antibodies to myelin-associated glycoprotein. It is thought that the IgMs are directed at myelin-associated glycoprotein epitopes on peripheral nerve constituents, and thereby are possibly pathogenic. GBS is not associated with monoclonal gammopathies.

Although the confirmation of GBS or CIDP primarily rests on clinical features, CSF analysis, EMG (see Fig. 72-8), serum immunophoresis, and treatment response provide the best means to make a precise diagnosis. An increased level of CSF protein (>50 mg/dL) without pleocytosis (<10 cells/mm³) is common in GBS and CIDP. CSF examination is often normal within the first week of GBS; however, approximately 90% of patients with CIDP and patients with late GBS have an increased level of CSF protein. Although 10–50 cells/mm³ in the CSF may occur in GBS, more than 50 cells/mm³ must arouse suspicion of an alternate diagnosis, including Lyme neuroborreliosis, HIV-associated polyradiculoneuropathy, poliomyelitis, or lymphomatous meningoradiculitis.

EMG provides a definitive means to assess the presence of a peripheral neuropathic process, ruling out other causes such as disorders of neuromuscular transmission or myopathy. EMG can demonstrate widespread involvement of spinal roots and peripheral nerves, usually defining the process as demyelinating, although well-recognized axonal variants exist with GBS as noted above. In GBS or CIDP, the motor and sensory conduction velocities are abnormally slow, with prolonged distal motor and F-wave latencies and often absent H reflexes. Nonuniform slowing, conduction block at sites not prone to entrapment, and abnormal temporal dispersion are commonly found in GBS and CIDP but not in most inherited demyelinating polyneuropathies. Conduction block is present when there are significant reductions in compound motor nerve action potential amplitude and area, with proximal versus distal stimulation. Temporal dispersion is characterized by abnormal prolongation of compound motor nerve action potential duration with proximal but not distal stimulation. Conduction velocities on routine nerve conduction studies may be normal when inflammatory lesions are more proximal, for example, in nerve roots or early in the disease course. Documentation of absent F waves, conduction block, temporal dispersion, or a combination of these is helpful for diagnosis of early GBS wherein more widespread slowing of conduction is not yet present. Another important feature of the electrodiagnostic studies can be the pattern of “sural sparing,” which means there is a normal sural sensory response in the setting of abnormal median and sensory antidromic sensory responses; this may be seen in CIDP.

Usually, blood laboratory study results are unremarkable in GBS and CIDP. The most important exception is the occasional occurrence of a monoclonal protein in patients with CIDP; this usually represents a monoclonal gammopathy of undetermined significance. When this is a λ monoclonal antibody, it may signify a malignancy, such as osteosclerotic or osteolytic myeloma in POEMS as noted above, multiple myeloma, or Waldenström macroglobulinemia.

Treatment

Care of patients with GBS varies from watchful waiting to emergency intervention, but initially always in a hospital because of the potential for rapid respiratory compromise. Patients with mild GBS who are able to ambulate are often cared for without specific treatment. Those individuals who are unable to walk, who develop respiratory compromise, or who exhibit rapid progression require treatment with plasmapheresis (PE) or IVIG. Both treatments are effective, but only if given within 1–2 weeks of onset, when the autoimmune attack is still active. Concomitant or sequential use of these therapies usually has no value. IVIG is given as a 2.0 g/kg dosage over 2–5 days. PE is given as five plasma exchanges of 1 plasma volume each over 9–10 days. Oral steroids are not effective for GBS. Respiratory failure is common in GBS; one third of patients require mechanical ventilation. Early on in the course of GBS, negative inspiratory force and vital capacity must be monitored closely in all patients. Autonomic dysfunction is also seen frequently. Labile hypertension and arrhythmias occur frequently, often prompting observation and management in the intensive care unit.

Treatment of patients with CIDP having significant disability with oral corticosteroids, IVIG, and PE is useful. Predetermined neurologic end points, such as strength, gait, and reflexes, must be monitored closely. In CIDP, clinical improvement usually occurs within a few weeks. Oral steroids, usually prednisone, are also efficacious in CIDP. The initial dose is usually 40–60 mg/day, transitioned to every-other-day dosing, then tapered and discontinued. The potential acute and chronic risks must be considered when deciding on steroid treatment and its duration. PE is not used as frequently as oral steroids or IVIG for CIDP because it is more invasive and not any more efficacious. In addition, the response to PE may be more transient. Nonetheless, PE remains an option, especially for patients who do not respond to IVIG or steroids.

Most patients with GBS have a good prognosis, particularly those who primarily have the disorder limited to demyelination without significant axonal involvement where the course may be more prolonged. Most recover within a few months, although recovery is not always complete. A small percentage is left with some disability, and rarely, permanent disability primarily involving distal weakness in the feet. Occasional (approximately 1–2%) mortalities do occur in GBS. Most deaths are from preventable respiratory complications or autonomic derangement. Supportive care, including emotional and nutritional support, judicious pain management, and prophylaxis for common complications of hospitalized, immobile patients (deep venous thrombosis and decubitus ulcers) is important.

The long-term outcome varies for patients with CIDP who are treated with conventional therapy. Most return to normal strength although some require intermittent IVIG to maintain improvement. Unfortunately, a rare patient progresses despite aggressive immunotherapy.

Sensory Neuronopathies

Clinical Vignette

A 64-year-old lifelong smoker awakened with unexplained, poorly described pain in her left groin unrelated to position or movement. Within 2 weeks, pains developed in a multifocal distribution. Her feet, her hands, and the right posterior part of her scalp became numb. She experienced increasing difficulty maintaining balance and walking, particularly in the dark or with her eyes closed.

Examination revealed a chronically ill woman who initially seemed to give incomplete effort during manual muscle testing. This was corrected by having her directly visualize tested body parts. Muscle stretch reflexes were absent in the ankles and knees and diminished but present in the arms. Vibration, position, and, to a lesser extent, pain and temperature sensations were absent in the feet and variously diminished more proximally. Pinprick was less well perceived in the right posterior part of the scalp than in the left.

Within 2 months of onset, the patient could not open her mouth and reported blurred vision. Examination disclosed apparent trismus and a direction-changing nystagmus. EMG revealed absent sensory nerve action potentials in the lower extremities and reduced sensory nerve action potentials in the hands. Motor conduction and needle electrode examination results were normal.

An acute-onset sensory polyneuropathy developed in this patient. Her clinical profile suggested a non–length-dependent process typical of a dorsal root ganglion cell sensory neuronopathy. This rapid temporal evolution in a smoker was a particularly ominous sign suggestive of a paraneoplastic sensory neuronopathy. Her subsequent development of trismus and nystagmus suggested concomitant brainstem encephalitis, another paraneoplastic syndrome that occurs in patients with small cell lung cancer. Chest imaging and subsequent biopsy of an anterior mediastinal mass confirmed the suspected small cell lung cancer. Anti-Hu antibodies confirmed the paraneoplastic relation between the sensory neuronopathy and lung tumor.

Most patients with peripheral neuropathies present with slowly ingravescent sensory symptoms and signs typical of a length-dependent polyneuropathy (LDPN). Another, smaller population of sensory-impaired individuals has pathophysiology primarily affecting the sensory neuron cells within the dorsal root ganglion (in contrast to neuropathies, affecting the distal nerve axon) (Fig. 72-11). They are described as having a primary sensory neuronopathy. The acute onset is often typified by a painful, noxious clinical picture with a generalized distribution. The dorsal root ganglia (DRG) sensory peripheral nerve cell bodies are the primary target of the disease process in patients with sensory neuronopathies. This anatomic locale explains why these disorders present with a non–length-dependent clinical pattern. Disproportionate loss of position and other discriminatory modalities occur when large sensory fibers are affected. Severe sensory ataxia frequently presents. Distinguishing between sensory LDPN and sensory neuronopathy is important because their differential diagnoses vary considerably. Often, a clinically suspected diagnosis can be confirmed with EMG.

Figure 72-11 Spinal Nerve Origin: Sensory Components.

In paraneoplastic sensory neuronopathy (PSN), it is proposed that similar molecular and antigenic components in DRG and small cell lung carcinoma cells set the stage for molecular mimicry. PSN typically has an acute to subacute painful presentation. It occurs in approximately 1% of patients with small cell lung cancer, rarely with other malignancies. The paraneoplastic syndrome may precede malignancy recognition by years. One or more additional paraneoplastic neurologic syndromes eventually develop in approximately 75% of these patients.

Sjögren syndrome is an immunologically mediated process associated with several neuropathy phenotypes that may evolve acutely or chronically. The classic sensory neuronopathy form is uncommon. It is clinically indistinguishable from other DRG lesions, particularly paraneoplastic sensory neuronopathy. Women are more commonly affected. Diagnostic findings include the sicca complex with dry eyes and mouth, antibodies directed against SSA and SSB, inflammatory involvement of salivary glands on lip biopsy, or a combination of these.

Sensory neuronopathy is a well-recognized dose-related and dose-limiting toxicity of cisplatin and carboplatin. Pyridoxine in large doses (1–2 g daily) may cause irreversible sensory neuronopathy syndromes. Doses, as small as 200 mg/day, over extended periods may have similar toxic potential. Vitamin B₁₂ deficiency and tabes dorsalis have strong predispositions to affect the posterior columns. They present with sensory ataxia. Patients with B₁₂ deficiency frequently experience paresthesias, often initially in the hand in a non–length-dependent manner, but may also have generalized painful neuropathies. Tabes dorsalis is rarely seen today. This complication of tertiary syphilis is typified by its unusual clinical manifestations, including paroxysms of severely uncomfortable lightning pains and ataxia. Many sensory neuronopathy patients with ataxic neuropathies do not have definable pathophysiologic mechanisms, idiopathic sensory ganglionopathy. As with idiopathic or cryptogenic disease categories, this remains a diagnosis of exclusion. Often clinically indistinguishable from paraneoplastic sensory neuronopathy presenting with a sensory ataxia, these disorders may evolve acutely or chronically and occur predominantly in women.

EMG is the initial study because it provides a means to differentiate between LDPN and sensory neuronopathy. Almost all patients with LDPNs, even those without clinical weakness, have EMG evidence of motor involvement. These are recognized by motor nerve conduction study changes, needle electrode examination abnormalities, or both (Fig. 72-12). Patients with a primary DRG lesion, that is, sensory neuronopathy, have only sensory nerve conduction study abnormalities.

Figure 72-12 Hereditary Sensory Neuropathy.

When sensory neuronopathies are confirmed, subsequent ancillary testing is limited to disorders known to cause such patterns (Box 72-6). The various causes of sensory LDPN may also require consideration (Box 72-7). Testing for serum anti-Hu antibodies is indicated in sensory neuronopathy evaluation, particularly for patients with a smoking or asbestos-exposure history. They are sensitive and specific for paraneoplastic neurologic disorders, particularly those with occult malignancies such as small cell lung cancer. Chest CT is indicated because the neuropathy may precede malignancy recognition by several years. Patients with suspected Sjögren syndrome require serologic tests, particularly SSA and SSB antibodies. Other potentially beneficial studies include the Schirmer test of lacrimation and slit lamp examination of the conjunctiva after Rose-Bengal staining. Minor salivary gland (usually lip) biopsy is performed if the diagnosis remains unconfirmed with less invasive means. Vitamin B₁₂ levels and a serologic test for syphilis are important for evaluation of patients with large-fiber sensory dysfunction. When the vitamin B₁₂ level is borderline, the more sensitive blood or urine tests for homocysteine, methylmalonic acid, or both are helpful. A nerve biopsy is usually not indicated in sensory neuronopathies.