3474 PART 13 Neurologic Disorders

Autologous hematopoietic stem cell transplantation appears to be

highly effective in reducing the occurrence of relapses and may

improve disability in relapsing MS. It appears to be ineffective for

patients with progressive MS. Stem cell transplantation also carries

significant risk, and randomized trials with appropriate comparators

are needed in order to position this procedure with respect to available

pharmacologic interventions.

■ PROMISING EXPERIMENTAL THERAPIES

Numerous clinical trials of promising experimental therapies are currently underway. These include studies of molecules to promote remyelination; autologous hematopoietic stem cell transplantation; higher

doses of ocrelizumab; and selective kinase inhibitors including Bruton’s

tyrosine kinase (BTK).

OTHER THERAPEUTIC CLAIMS

Many purported treatments for MS have never been subjected to scientific scrutiny. These include dietary therapies (e.g., the Swank diet,

the Paleo diet, the Wahls diet), megadose vitamins, calcium orotate,

bee stings, cow colostrum, hyperbaric oxygen, procarin (a combination of histamine and caffeine), chelation, acupuncture, acupressure,

various Chinese herbal remedies, and removal of mercury-amalgam

tooth fillings, among many others. Patients should avoid costly or

potentially hazardous unproven treatments. Many such treatments lack

biologic plausibility. No reliable case of mercury poisoning resembling

typical MS has ever been described, therefore challenging the notion

that removal of mercury-amalgam tooth fillings would be beneficial.

Although potential roles for EBV, human herpesvirus (HHV) 6, or

chlamydia have been suggested for MS, treatment with antiviral agents

or antibiotics is not recommended. A chronic cerebrospinal insufficiency (CCSVI) was proposed as a cause of MS with vascular-surgical

intervention recommended. However, multiple independent studies

have failed to even approximate the initial claims, and patients should

be strongly advised to avoid diagnostic procedures and potentially dangerous surgery for this condition. A double-blind trial of high-dose biotin to improve disability in progressive forms of MS found no benefit.

SYMPTOMATIC THERAPY

For all patients, it is important to encourage attention to a healthy lifestyle, including maintaining an optimistic outlook, a healthy diet, and

regular exercise as tolerated (swimming is often well-tolerated because

of the cooling effect of cold water). It is reasonable also to correct

vitamin D deficiency with oral vitamin D.

Ataxia/tremor is often intractable. Clonazepam, 1.5–20 mg/d;

primidone, 50–250 mg/d; propranolol, 40–200 mg/d; or ondansetron,

8–16 mg/d, may help. Wrist weights occasionally reduce tremor in the

arm or hand. Thalamotomy and deep-brain stimulation have been

tried with mixed success.

Spasticity and spasms may improve with physical therapy, regular

exercise, and stretching. Avoidance of triggers (e.g., infections, fecal

impactions, bed sores) is extremely important. Effective medications

include baclofen (20–120 mg/d), diazepam (2–40 mg/d), tizanidine

(8–32 mg/d), dantrolene (25–400 mg/d), and cyclobenzaprine hydrochloride (10–60 mg/d). For severe spasticity, a baclofen pump (delivering medication directly into the CSF) can provide substantial relief.

Weakness can sometimes be improved with the use of potassium channel blockers such as 4-aminopyridine (20 mg/d) and

3,4-di-aminopyridine (40–80 mg/d), particularly in the setting where

lower-extremity weakness interferes with the patient’s ability to ambulate. The FDA approved extended-release 4-aminopyridine (at 10 mg

twice daily), and this can be obtained either as dalfampridine (Ampyra)

or through a compounding pharmacy. The principal concern with the

use of these agents is the possibility of inducing seizures at high doses.

Pain is treated with anticonvulsants (carbamazepine, 100–1000 mg/d;

phenytoin, 300–600 mg/d; gabapentin, 300–3600 mg/d; or pregabalin,

50–300 mg/d), antidepressants (amitriptyline, 25–150 mg/d; nortriptyline, 25–150 mg/d; desipramine, 100–300 mg/d; or venlafaxine,

75–225 mg/d), or antiarrhythmics (mexiletine, 300–900 mg/d). If

these approaches fail, patients should be referred to a comprehensive

pain-management program.

Bladder dysfunction management is best guided by urodynamic

testing. Evening fluid restriction or frequent voluntary voiding may

help detrusor hyperreflexia. If these methods fail, propantheline

bromide (10–15 mg/d), oxybutynin (5–15 mg/d), hyoscyamine sulfate (0.5–0.75 mg/d), tolterodine tartrate (2–4 mg/d), or solifenacin

(5–10 mg/d) may help. Coadministration of pseudoephedrine

(30–60 mg) is sometimes beneficial.

Detrusor/sphincter dyssynergia may respond to phenoxybenzamine

(10–20 mg/d) or terazosin hydrochloride (1–20 mg/d). Loss of reflex

bladder wall contraction may respond to bethanechol (30–150 mg/d).

However, both conditions often require catheterization.

Urinary tract infections should be treated promptly. Patients with

postvoid residual urine volumes >200 mL are predisposed to infections. Prevention by urine acidification (with cranberry juice or

vitamin C) inhibits some bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to colonization by resistant

organisms. Intermittent catheterization may help to prevent recurrent

infections and reduce overflow incontinence.

Treatment of constipation includes high-fiber diets and fluids. Natural or other laxatives may help. Fecal incontinence may respond to a

reduction in dietary fiber.

Depression should be treated. Useful drugs include the selective

serotonin reuptake inhibitors (fluoxetine, 20–80 mg/d, or sertraline,

50–200 mg/d), the tricyclic antidepressants (amitriptyline, 25–150 mg/d;

nortriptyline, 25–150 mg/d; or desipramine, 100–300 mg/d), and the

nontricyclic antidepressants (venlafaxine, 75–225 mg/d).

Fatigue may improve with assistive devices, help in the home, or

successful management of spasticity. Patients with frequent nocturia

may benefit from anticholinergic medication at bedtime. Excessive

daytime somnolence caused by MS may respond to amantadine

(200 mg/d), methylphenidate (5–25 mg/d), modafinil (100–400 mg/d),

or armodafinil (150–250 mg/d).

Cognitive problems may respond marginally to lisdexamfetamine

(40 mg/d).

Paroxysmal symptoms respond dramatically to low-dose anticonvulsants (acetazolamide, 200–600 mg/d; carbamazepine, 50–400 mg/d;

phenytoin, 50–300 mg/d; or gabapentin, 600–1800 mg/d).

Heat sensitivity may respond to heat avoidance, air-conditioning, or

cooling garments.

Sexual dysfunction may be helped by lubricants to aid in genital

stimulation and sexual arousal. Management of pain, spasticity, fatigue,

and bladder/bowel dysfunction may also help. Sildenafil (50–100 mg),

tadalafil (5–20 mg), or vardenafil (5–20 mg), taken 1–2 h before sex,

are standard treatments for erectile dysfunction.

CLINICAL VARIANTS OF MS

Acute MS (Marburg’s variant) is a fulminant demyelinating process

that in some cases progresses inexorably to death within 1–2 years.

Typically, there are no remissions. Marburg’s variant does not seem to

follow infection or vaccination, and it is unclear whether this syndrome

represents an extreme form of MS or another disease altogether. When

an acute demyelinating syndrome presents as a solitary expansile

lesion, a brain tumor is often suspected (Fig. 444-4). Such cases are

designated tumefactive MS, and a brain biopsy may be required to

establish the diagnosis.

Balo’s concentric sclerosis is another fulminant demyelinating syndrome characterized by concentric brain or spinal cord lesions with

alternating spheres of demyelination and remyelination (Fig. 444-4).

For these fulminant demyelinating states, no controlled trials of therapy exist; high-dose glucocorticoids, plasma exchange, and cyclophosphamide have been tried, with uncertain benefit.

ACUTE DISSEMINATED

ENCEPHALOMYELITIS (ADEM)

ADEM has a monophasic course and is most frequently associated

with an antecedent infection (postinfectious encephalomyelitis); ~5%

of ADEM cases follow immunization (postvaccinal encephalomyelitis).

ADEM is far more common in children than adults, and many adult

cases initially thought to represent ADEM subsequently experience

3475 Multiple Sclerosis CHAPTER 444

A B

C D

FIGURE 444-4 Magnetic resonance imaging findings in variants of MS. A and B. Acute tumefactive MS. In A, a sagittal T2-weighted fluid-attenuated inversion recovery

(FLAIR) image of a large solitary right parieto-occipital white matter lesion is shown, with effacement of overlying cortical sulci consistent with mass effect. In B,

T1-weighted image obtained after the intravenous administration of gadolinium DTPA reveals a large serpiginous area of blood-brain barrier disruption consistent with

acute inflammation. C and D. Balo’s concentric sclerosis. In C, an axial T2-weighted sequence shows multiple areas of abnormal ovoid bright signal in the supratentorial

white matter bilaterally; some lesions reveal concentric layers, typical of Balo’s concentric sclerosis. In D, T1-weighted MR images postgadolinium demonstrate abnormal

enhancement of all lesions with some lesions demonstrating concentric ring enhancement.

late relapses qualifying as either MS or another chronic inflammatory

disorder such as vasculitis, sarcoidosis, or lymphoma. The hallmark of

ADEM is the presence of widely scattered foci of perivenular inflammation and demyelination that can involve both white matter and grey

matter structures, in contrast to larger confluent white matter lesions

typical of MS. In the most explosive form of ADEM, acute hemorrhagic

leukoencephalitis, the lesions are vasculitic and hemorrhagic, and the

clinical course is devastating.

Postinfectious encephalomyelitis is most frequently associated with

the viral exanthems of childhood. Infection with measles virus is

the most common antecedent (1 in 1000 cases). Worldwide, measles

encephalomyelitis is still common, although use of the live measles

3476 PART 13 Neurologic Disorders

vaccine has dramatically reduced its incidence in developed countries.

An ADEM-like illness rarely follows vaccination with live measles

vaccine (1–2 in 106

 immunizations). ADEM is now most frequently

associated with varicella (chickenpox) infections (1 in 4000–10,000

cases). It may also follow infection with rubella, mumps, influenza,

parainfluenza, EBV, HHV-6, HIV, dengue, Zika, other viruses, and

Mycoplasma pneumoniae. Recently, cases have been described in

association with COVID-19 infection. Some patients may have a nonspecific upper respiratory infection or no known antecedent illness. In

addition to measles, postvaccinal encephalomyelitis may also follow

the administration of vaccines for smallpox (5 cases per million), the

Semple rabies, and Japanese encephalitis. Modern vaccines that do not

require viral culture in CNS tissue have reduced the ADEM risk.

All forms of ADEM presumably result from a cross-reactive immune

response to the infectious agent or vaccine that then triggers an inflammatory demyelinating response. Autoantibodies to MBP and to other

myelin antigens have been detected in the CSF from some patients

with ADEM, and approximately half of children with ADEM have

circulating and CSF antibodies against MOG (Chap. 445). Attempts to

demonstrate direct viral invasion of the CNS have been unsuccessful.

CLINICAL MANIFESTATIONS

In severe cases, onset is abrupt and progression rapid (hours to days). In

postinfectious ADEM, the neurologic syndrome generally begins late

in the course of the viral illness as the exanthem is fading. Fever reappears, and headache, meningismus, and lethargy progressing to coma

may develop. Seizures are common. Signs of disseminated neurologic

disease are consistently present (e.g., hemiparesis or quadriparesis,

extensor plantar responses, lost or hyperactive tendon reflexes, sensory loss, and brainstem involvement). In ADEM due to chickenpox,

cerebellar involvement is often conspicuous. CSF protein is modestly

elevated (0.5–1.5 g/L [50–150 mg/dL]). Lymphocytic pleocytosis,

generally ≥200 cells/μL, occurs in 80% of patients. Occasional patients

have higher counts or a mixed polymorphonuclear-lymphocytic pattern during the initial days of the illness. Transient CSF oligoclonal

banding has been reported. MRI usually reveals extensive changes in

the brain and spinal cord, consisting of white matter hyperintensities

on T2 and fluid-attenuated inversion recovery (FLAIR) sequences with

Gd enhancement on T1-weighted sequences.

DIAGNOSIS

The diagnosis is most reliably established when there is a history

of recent vaccination or viral exanthematous illness. In severe cases

with predominantly cerebral involvement, acute encephalitis due to

infection with herpes simplex or other viruses including HIV may

be difficult to exclude; other considerations include hypercoagulable

states including the antiphospholipid antibody syndrome, autoimmune

(paraneoplastic) limbic encephalitis, vasculitis, neurosarcoid, primary

CNS lymphoma, or metastatic cancer. An explosive presentation of

MS can mimic ADEM, and, especially in adults, it may not be possible

to distinguish these conditions at onset. The simultaneous onset of

disseminated symptoms and signs is common in ADEM and rare in

MS. Similarly, meningismus, drowsiness, coma, and seizures suggest

ADEM rather than MS. Unlike MS, in ADEM, optic nerve involvement

is generally bilateral and transverse myelopathy complete. MRI findings that favor ADEM include extensive and relatively symmetric white

matter abnormalities, basal ganglia or cortical gray matter lesions,

and Gd enhancement of all abnormal areas. By contrast, OCBs in the

CSF are more common in MS. In one study of adult patients initially

thought to have ADEM, 30% experienced additional relapses over a

follow-up period of 3 years, and they were reclassified as having MS.

Other patients initially classified as ADEM are subsequently found to

have neuromyelitis optica spectrum disorder (Chap. 445). Occasional

patients with “recurrent ADEM” have also been reported, especially

children; however, it is not possible to distinguish this entity from atypical MS. Because of the clinical overlap at presentation between ADEM

and MS, it is crucial that routine surveillance imaging be performed

following recovery from ADEM so that subclinical disease activity due

to MS can be recognized and treatment for MS initiated.

TREATMENT

■ ACUTE DISSEMINATED ENCEPHALOMYELITIS

Initial treatment is with high-dose glucocorticoids; depending on the

response, treatment may need to be continued for 8 weeks. Patients

who fail to respond within a few days may benefit from a course of

plasma exchange or intravenous immunoglobulin. The prognosis

reflects the severity of the underlying acute illness. In recent case series

of presumptive ADEM in adults, mortality rates of 5–20% are reported,

and many survivors have permanent neurologic sequelae.

GLIAL FIBRILLARY ACIDIC PROTEIN

(GFAP) AUTOIMMUNITY

Autoimmunity against the astrocyte protein GFAP presents with a

range of symptoms referable to meningismus, encephalitis, myelitis,

and optic neuritis. MRI shows characteristic patterns of gadolinium

enhancement localized to GFAP-enriched CNS regions including

venous structures in a periventricular radial orientation, the leptomeninges, the peri-ependymal spinal cord, and a striking serpiginous

pattern involving brain parenchyma. These enhancement patterns

share some similarities with patterns that can be observed in neurosarcoidosis. The presence of these patterns should prompt consideration

for either condition. A lymphocytic pleocytosis is commonly present

in the CSF. Antibodies against GFAP can be measured in the CSF or

serum. GFAP autoimmunity is found as a paraneoplastic syndrome

in 25% of cases, most commonly associated with ovarian teratoma,

and can coexist with anti-N-methyl-d-aspartate receptor (NMDAR)

encephalitis or neuromyelitis optica spectrum disorder (NMOSD).

T cells are implicated in pathophysiology based on histopathology

and association with checkpoint inhibitor treatment for cancer or in

the setting of HIV. GFAP autoimmunity is generally glucocorticoid

responsive. Early recognition with prompt intervention is associated

with more favorable outcomes. Relapses occur in approximately 20%

of patients and require use of immune suppression therapy.

■ FURTHER READING

Absinta M et al: Mechanisms underlying progression in multiple sclerosis. Curr Opin Neurol 33:277, 2020.

Bevan RJ et al: Meningeal inflammation and cortical demyelination in

acute multiple sclerosis. Ann Neurol 84:829, 2018.

Brown JWL et al: Association of initial disease-modifying therapy

with later conversion to secondary progressive multiple sclerosis.

JAMA 321:175, 2019.

Cree BAC et al: Silent progression in disease activity-free relapsing

multiple sclerosis. Ann Neurol 85:653, 2019.

Giovannoni G et al: Alemtuzumab improves preexisting disability

in active relapsing-remitting MS patients. Neurology 87:1985, 2016.

Hauser SL et al: Ocrelizumab versus interferon beta-1a in relapsing

multiple sclerosis. N Engl J Med 376:221, 2017.

Hauser SL et al: Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med 383:546, 2020.

Luna G et al: Infection risks among patients with multiple sclerosis

treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol 77:184, 2020.

Malpas CB et al: Early clinical markers of aggressive multiple sclerosis.

Brain 143:1400, 2020.

Naegelin Y et al: Association of rituximab treatment with disability

progression among patients with secondary progressive multiple

sclerosis. JAMA Neurol 76:274, 2019.

Montalban X et al: Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 376:209, 2017.

Pohl D et al: Acute disseminated encephalomyelitis: Updates on an

inflammatory CNS syndrome. Neurology 87(9 Suppl 2):S38, 2016.

Shan F et al: Autoimmune glial fibrillary acidic protein astrocytopathy:

A review of the literature. Front Immunol 9:2802, 2018.

Thompson AJ et al: Diagnosis of multiple sclerosis: 2017 revisions of

the McDonald criteria. Lancet Neurol 17:162, 2018.

Zamvil SS, Hauser SL: Antigen presentation by B cells in multiple

sclerosis. [Review] N Engl J Med 384:378, 2021.

3477 Neuromyelitis Optica CHAPTER 445

INTRODUCTION

Neuromyelitis optica (NMO; Devic’s disease) is an aggressive inflammatory disorder characterized by recurrent attacks of optic neuritis

(ON) and myelitis; the more inclusive term NMO spectrum disorder

(NMOSD) was proposed to include individuals with partial forms, and

also those with involvement of additional regions in the central nervous system (Table 445-1). NMO is more frequent in women than men

(9:1), and typically begins in adulthood, with a mean age of onset of

40 years, but can arise at any age. An important consideration, especially early in its presentation, is distinguishing NMO from multiple

sclerosis (MS; Chap. 444). In patients with NMO, attacks of ON can be

bilateral and produce severe visual loss (uncommon in MS); myelitis

can be severe and transverse (rare in MS) and is typically longitudinally

extensive (Fig. 445-1), involving three or more contiguous vertebral

segments. In contrast to MS, progressive symptoms typically do not

occur in NMO. The brain MRI was earlier thought to be normal in

NMO, but it is now recognized that in many cases brain lesions are

present, including areas of nonspecific signal change as well as lesions

445

associated with specific syndromes such as the hypothalamus causing

an endocrinopathy; the area postrema in the lower medulla presenting

as intractable hiccups or vomiting; or the cerebral hemispheres producing focal symptoms, encephalopathy, or seizures. Large MRI lesions

in the cerebral hemispheres can be asymptomatic, sometimes have a

“cloudlike” appearance and, unlike MS lesions, are often not destructive

and can resolve completely. Spinal cord MRI lesions typically consist of

focal enhancing areas of swelling and tissue destruction, extending

over three or more spinal cord segments, and on axial sequences, these

are centered on the grey matter of the cord. Cerebrospinal fluid (CSF)

findings include pleocytosis greater than that observed in MS, with

neutrophils and eosinophils present in many acute cases; oligoclonal

bands (OCBs) are uncommon, occurring in <20% of NMO patients.

The pathology of NMO is a distinctive astrocytopathy with inflammation, loss of astrocytes, and an absence of staining of the water channel

protein AQP4 by immunohistochemistry, plus thickened blood vessel

walls, demyelination, and deposition of antibody and complement.

IMMUNOLOGY

NMO is an autoimmune disease associated with a highly specific autoantibody directed against aquaporin-4 (AQP-4) that is present in the

sera of ~90% of patients with a clinical diagnosis of NMO. AQP-4 is

localized to the foot processes of astrocytes in close apposition to endothelial surfaces, as well as at paranodal regions near nodes of Ranvier.

It is likely that AQP-4 antibodies are pathogenic because their passive

transfer into laboratory animals can reproduce histologic features

of the disease. Antibody-mediated complement fixation is thought

to represent the primary mechanism of astrocyte injury in NMO.

During acute attacks of myelitis, CSF levels of interleukin-6 (IL-6; a

proinflammatory cytokine) and astrocyte-specific glial fibrillary acidic

protein (GFAP) levels are markedly elevated, consistent with active

inflammation and astrocyte injury. Proinflammatory T-lymphocytes

of the Th17 type recognize an immunodominant epitope of AQP4 and

may also contribute to pathogenesis. Because of the high specificity of

the antibody, its presence is considered to be diagnostic when found

in conjunction with a typical clinical presentation. Anti-AQP4 seropositive patients have a high risk for future relapses; more than half of

untreated patients will relapse within 1 year.

CLINICAL COURSE

NMO is typically a recurrent disease; the course is monophasic in <10%

of patients. Individuals who test negative for AQP4 antibodies are somewhat more likely to have a monophasic course. Untreated NMO is usually

quite disabling over time; in one series, respiratory failure from cervical

myelitis was present in one-third of patients, and 8 years after onset,

60% of patients were blind and more than half had permanent paralysis

of one or more limbs. The long-term course of NMO appears to have

been substantially improved with the development of therapies to treat

acute attacks and prevent relapses. Estimates of the 5-year survival rate

increased from 68–75% in 1999 to 91–98% in 2017, a change likely due

to improved diagnosis and widespread use of immunosuppressant drugs.

GLOBAL CONSIDERATIONS

The incidence and prevalence of NMO show considerable variation

between populations and geographic regions, with prevalence estimates that range from <1 to > 4 per 100,000. Although NMO can occur

in people of any ethnic background, individuals of Asian and African

origin are disproportionately affected. The highest reported prevalence

is from Martinique. Among white populations, MS (Chap. 444) is far

more common than NMO.

Interestingly, when MS affects individuals of African or Asian

ancestry, there is a propensity for demyelinating lesions to involve

predominantly the optic nerve and spinal cord, an MS subtype termed

opticospinal MS. Some individuals with opticospinal MS are seropositive for AQP4 antibodies, indicating that such cases represent NMOSD.

ASSOCIATED CONDITIONS

Up to 40% of NMO patients have a systemic autoimmune disorder, such

as systemic lupus erythematosus, Sjögren’s syndrome, perinuclear antineutrophil cytoplasmic antibody (p-ANCA)–associated vasculitis, myasthenia

Neuromyelitis Optica

Bruce A. C. Cree, Stephen L. Hauser

TABLE 445-1 Diagnostic Criteria for Neuromyelitis Optica

Spectrum Disorder

Diagnostic Criteria for NMOSD with AQP4-IgG

1. At least 1 core clinical characteristic

2. Positive test for AQP4-IgG using best-available detection method (cell-based

assay strongly recommended)

3. Exclusion of alternative diagnoses

Diagnostic Criteria for NMOSD Without AQP4-IgG or NMOSD with

Unknown AQP4-IgG Status

1. At least 2 core clinical characteristics occurring as a result of one or more

clinical attacks and meeting all of the following requirements:

a. At least 1 core clinical characteristic must be optic neuritis, acute myelitis

with LETM, or area postrema syndrome

b. Dissemination in space (2 or more different clinical characteristics)

c. Fulfillment of additional MRI requirements, as applicable

2. Negative test for AQP4-IgG using best-available detection method or testing

unavailable

3. Exclusion of alternative diagnoses

Core Clinical Characteristics

1. Optic neuritis

2. Acute myelitis

3. Area postrema syndrome: episode of otherwise unexplained hiccups or

nausea or vomiting

4. Acute brainstem syndrome

5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with

NMOSD-typical diencephalic MRI lesions

6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions

Additional MRI Requirements for NMOSD Without AQP4-IgG and

NMOSD with Unknown AQP4-IgG Status

1. Acute optic neuritis: requires brain MRI showing (a) normal findings

or only nonspecific white matter lesions, OR (b) optic nerve MRI with

T2-hyperintense lesion of T1-weighted gadolinium-enhancing lesion

extending over >1/2 optic nerve length or involving optic chiasm

2. Acute myelitis: requires associated intramedullary MRI lesion extending ≥3

contiguous segments (LETM) OR ≥3 contiguous segments of focal spinal cord

atrophy in patients with history compatible with acute myelitis

3. Area postrema syndrome requires associated dorsal medulla/area postrema

lesions

4. Acute brainstem syndrome requires periependymal brainstem lesions

Source: Reproduced with permission from DM Wingerchuk et al: International

consensus diagnostic criteria for neuromyelitis optica spectrum disorders.

Neurology 85:177, 2015.

3478 PART 13 Neurologic Disorders

A B

C D

E F

FIGURE 445-1 Imaging findings in neuromyelitis optica: longitudinally extensive transverse myelitis, optic neuritis, and brainstem involvement. A. Sagittal fluid attenuation

inversion recovery (FLAIR) cervical-spine MRI showing an area of increased signal change on T2-weighted imaging spanning >3 vertebral segments in length. B. Sagittal

T1-weighted cervical-spine MRI following gadolinium-diethylene triamine pentaacetic acid (DPTA) infusion showing enhancement. C. Coronal brain MRI shows hyperintense

signal on FLAIR imaging within the left optic nerve. D. Coronal T1-weighted brain MRI following gadolinium-DPTA infusion shows enhancement of the left optic nerve. E.

Axial brain MRI shows an area of hyperintense signal on T2-weighted imaging within the area postrema (arrow). F. Axial T1-weighted brain MRI following gadolinium-DPTA

infusion shows punctate enhancement of the area postrema (arrow).

gravis, Hashimoto’s thyroiditis, or mixed connective tissue disease. This is

another feature distinct from MS; MS patients rarely have other comorbid

autoimmune diseases with the exception of hypothyroidism. In some

NMO cases, onset may be associated with acute infection with varicella

zoster virus, Epstein-Barr virus, HIV, or tuberculosis. Rare cases appear to

be paraneoplastic and associated with breast, lung, or other cancers.

TREATMENT

Neuromyelitis Optica

Until recently, disease-modifying therapies were not rigorously studied in NMO. Acute attacks are usually treated

with high-dose glucocorticoids (e.g., methylprednisolone

1 g/d for 5–10 days followed by a prednisone taper). Plasma

exchange (typically 5–7 exchanges of 1.5 plasma volumes/exchange)

is used empirically for acute episodes that do not respond to glucocorticoids. Given the unfavorable natural history of untreated NMO,

prophylaxis against relapses is recommended for most patients

and several empiric regimens have been commonly used including: mycophenolate mofetil (1000 mg bid); the B-cell depleting

anti-CD20 monoclonal antibody rituximab (2 g IV Q 6 months); or

a combination of glucocorticoids (500 mg IV methylprednisolone

daily for 5 days; then oral prednisone 1 mg/kg per day for 2 months,

followed by slow taper) plus azathioprine (2 mg/kg per day started

on week 3). Importantly, some therapies with efficacy in MS do

not appear to be useful for NMO. Available evidence suggests that

interferon beta is ineffective and paradoxically may increase the

3479 Neuromyelitis Optica CHAPTER 445

risk of NMO relapses, and based on limited data glatiramer acetate,

fingolimod, natalizumab, and alemtuzumab also appear to be ineffective. These differences highlight the importance of distinguishing NMO from MS.

Three monoclonal antibody therapies have now received regulatory approval for attack prevention in NMO: eculizumab, a terminal

complement inhibitor; inebilizumab, a B-cell depleter; and satralizumab, an IL-6 receptor blocker (Table 445-2).

Eculizumab is a monoclonal antibody that binds to the complement protein C5, inhibiting its cleavage into C5a and C5b and

preventing generation of the terminal complement attack complex

C5b-9. Investigated as add-on therapy in AQP4 seropositive NMO,

eculizumab lengthened the time to first attack by 94%, reduced the

attack rate by 96%, and reduced rates of hospitalization, glucocorticoid, and plasma exchange use. Eculizumab is dosed as follows:

900 mg weekly for the first 4 weeks, followed by 1200 mg for the

fifth dose 1 week later, then 1200 mg every 2 weeks thereafter.

Eculizumab is available only through a restricted program under

a Risk Evaluation and Mitigation Strategy (REMS). Life-threatening and fatal meningococcal infections have occurred in eculizumab-treated patients (Boxed Warning). Eculizumab-treated

patients should be immunized with meningococcal vaccines at

least 2 weeks prior to administering the first dose unless the

risk of delaying eculizumab therapy outweigh the risk of developing a meningococcal infection. Vaccination reduces, but

does not eliminate, the risk of meningococcal infections. All

eculizumab-treated patients must be monitored for early signs of

meningococcal infections and evaluated immediately if infection

is suspected.

Inebilizumab is a humanized monoclonal antibody that binds

to the B-cell-specific surface antigen CD19 and depletes a wide

range of B cells including some plasmablasts as well as a proportion

of plasma cells in secondary lymphoid organs and bone marrow.

Inebilizumab used as monotherapy reduced time to the first NMO

attack by 77% compared to placebo, and also reduced hospitalizations by 78%, disability worsening by 63%, and new MRI lesions by

43%. Inebilizumab is dosed as follows: 300 mg IV infusion followed

2 weeks later by a second 300 mg IV infusion with subsequent doses

of 300 mg infusions every 6 months thereafter.

Inebilizumab is associated with a dose-dependent decline in

serum IgG levels and with neutropenia in some patients.

Satralizumab is a monoclonal antibody that binds to the

interleukin-6 receptor, blocking engagement of IL-6. Satralizumab

was investigated in NMOSD in two trials: one as monotherapy and

the other as add-on therapy. Both AQP4 seropositive and AQP4

seronegative participants were enrolled. In both studies, the time to

first attack was longer with satralizumab treatment compared with

placebo. The risk of attack was reduced by 74% in the monotherapy

study, and in the add-on study by 78%, with satralizumab. Although

both studies recruited substantial numbers of AQP4 seronegative

participants, there was no clinically meaningful impact of satralizumab in the seronegative participants. Satralizumab is administered as follows: a loading dosage of 120 mg by subcutaneous

injection at weeks 0, 2, and 4, followed by a maintenance dosage of

120 mg every 4 weeks.

Screening for hepatitis B virus, tuberculosis, and liver transaminase elevations is required before starting satralizumab.

Hepatic transaminases should be monitored during treatment for

transaminase elevation, and CBC should be monitored during

treatment for neutropenia. Satralizumab is also associated with

weight gain.

MYELIN OLIGODENDROCYTE

GLYCOPROTEIN-ANTIBODY-ASSOCIATED

DISEASE (MOGAD)

Although long considered to be a likely target for antibody-mediated

demyelination, anti-MOG antibodies detected by a cell-based assay

that enables recognition of myelin oligodendrocyte glycoprotein

(MOG) epitopes in a lipid bilayer were recently found to be associated with cases of acute disseminated encephalomyelitis (ADEM)

(Chap. 444) in children, and then with cases of AQP4 seronegative

NMO. Further studies showed that patients who are seropositive for

anti-MOG antibodies are at risk for bilateral, synchronous optic neuritis and myelitis. A clinical feature that can help distinguish ON associated with MOGAD from NMO or MS is the presence of papillitis seen

by funduscopy or orbital MRI. ON associated with MOGAD is typically longitudinally extensive on MRI, and brain MRI can be normal

or show fluffy areas of increased signal change in white or grey matter

structures, similar to NMO. MRI lesions that are typical for MS, including finger-like lesions oriented perpendicular to the ventricular surface

(Dawson fingers) and T1-hypointense lesions, are uncommon. Spinal

cord lesions can be longitudinally extensive or short and sometimes

involve the conus medullaris. Demyelination associated with MOGAD

is sometimes monophasic, as in ADEM, but can also be recurrent. The

CSF may show a pleocytosis with occasional neutrophils. Elevated

intrathecal synthesis of gammaglobulins is atypical: oligoclonal bands

are present in ~6–13% of cases and intrathecal synthesis of anti-MOG

antibodies does not occur. The mechanism of CNS injury in MOGAD

is not established. Studies in MOG-induced experimental autoimmune

encephalomyelitis suggest that anti-MOG antibodies may opsonize

traces of MOG protein in secondary lymphoid tissues, triggering an

encephalitogenic peripheral immune response.

Acute episodes are managed with high-dose glucocorticoids followed by a prednisone taper and sometimes by plasmapheresis, as with

NMO. Brain lesions associated with MOGAD often respond rapidly to

treatment with glucocorticoids and may resolve entirely. Some patients

experience disease recurrence following discontinuation of prednisone

and can become glucocorticoid dependent. Clinical trials have not

been undertaken and there is limited data on other immune-suppressing

medications typically used in NMO. Off-label empiric treatments

include daily prednisone, IVIg, rituximab, and mycophenolate mofetil.

Anti-MOG antibody titers appear to decline either spontaneously or in

the setting of treatment.

Rare cases of relapsing optic nerve and spinal cord disease resembling

NMOSD have recently been recognized in patients with autoantibodies against glial fibrillary acidic protein (GFAP), an astrocyte-specific

protein, although more commonly the disorder presents as a meningoencephalitis resembling acute disseminated encephalomyelitis. GFAP

astrocytopathy is discussed in Chap. 444.

■ FURTHER READING

Cree BAC et al: Inebilizumab for the treatment of neuromyelitis optica

spectrum disorder (N-MOmentum): A double-blind, randomised

placebo-controlled phase 2/3 trial. Lancet 394:1352, 2019.

Hinson SR et al: Autoimmune AQP4 channelopathies and neuromyelitis optica spectrum disorders. Handb Clin Neurol 133:377, 2016.

Marignier R et al: Myelin-oligodendrocyte glycoprotein antibodyassociated disease. Lancet Neurol 20:762, 2021.

Pittock SJ et al: Eculizumab in aquaporin-4-positive neuromyelitis

optica spectrum disorder. N Engl J Med 381:614, 2019.

Traboulsee A et al: Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised,

double-blind, multicentre, placebo-controlled phase 3 trial. Lancet

Neurol 19:402, 2020.

Wingerchuk DM et al: International consensus diagnostic criteria for

neuromyelitis optica spectrum disorders. Neurology 85:177, 2015.

TABLE 445-2 Therapeutic Trials for NMO

RISK REDUCTION IN AQP4-

SEROPOSITIVE PATIENTS

Eculizumab (add-on to immune

suppression)

94%, P<0.001

Inolimomab (monotherapy) 78%, P=0.01

Satralizumab (add-on to immune

suppression)

74%, P=0.001

Satralizumab (monotherapy) 77%, P<0.001

3480 PART 13 Neurologic Disorders

Peripheral nerves are composed of sensory, motor, and autonomic

elements. Diseases can affect the cell body of a neuron or its peripheral processes, namely the axons or the encasing myelin sheaths.

Most peripheral nerves are mixed and contain sensory and motor as

well as autonomic fibers. Nerves can be subdivided into three major

classes: large myelinated, small myelinated, and small unmyelinated. Motor axons are usually large myelinated fibers that conduct

rapidly (~50 m/s). Sensory fibers may be any of the three types.

Large-diameter sensory fibers conduct proprioception and vibratory

sensation to the brain, while the smaller-diameter myelinated and

unmyelinated fibers transmit pain and temperature sensation. Autonomic nerves are also small in diameter. Thus, peripheral neuropathies can impair sensory, motor, or autonomic function, either singly

or in combination. Peripheral neuropathies are further classified

into those that primarily affect the cell body (e.g., neuronopathy or

ganglionopathy), myelin (myelinopathy), and the axon (axonopathy). These different classes of peripheral neuropathies have distinct

clinical and electrophysiologic features. This chapter discusses the

clinical approach to a patient suspected of having a peripheral

neuropathy, as well as specific neuropathies, including hereditary

and acquired neuropathies. The inflammatory neuropathies are

discussed in Chap. 447.

GENERAL APPROACH

In approaching a patient with a neuropathy, the clinician has three main

goals: (1) identify where the lesion is, (2) identify the cause, and (3) determine the proper treatment. The first goal is accomplished by obtaining

a thorough history, neurologic examination, and electrodiagnostic and

other laboratory studies (Fig. 446-1). While gathering this information,

seven key questions are asked (Table 446-1), the answers to which help

identify the pattern of involvement and the cause of the neuropathy

(Table 446-2). Despite an extensive evaluation, in approximately half of

patients, no etiology is ever found; these patients typically have a predominately sensory polyneuropathy and have been labeled as having idiopathic or cryptogenic sensory and sensorimotor polyneuropathy (CSPN).

■ INFORMATION FROM THE HISTORY AND

PHYSICAL EXAMINATION: SEVEN KEY

QUESTIONS (TABLE 446-1)

1. What Systems Are Involved? It is important to determine if

the patient’s symptoms and signs are motor, sensory, autonomic, or a

combination of these. If the patient has only weakness without any evidence of sensory or autonomic dysfunction, a motor neuropathy, neuromuscular junction abnormality, or myopathy should be considered.

Some peripheral neuropathies are associated with significant autonomic

nervous system dysfunction. Symptoms of autonomic involvement

include fainting spells or orthostatic lightheadedness; heat intolerance;

or any bowel, bladder, or sexual dysfunction (Chap. 440). There will

typically be an orthostatic fall in blood pressure without an appropriate

increase in heart rate. Autonomic dysfunction in the absence of diabetes

should alert the clinician to the possibility of amyloid polyneuropathy.

Rarely, a pandysautonomic syndrome can be the only manifestation of

a peripheral neuropathy without other motor or sensory findings. The

majority of neuropathies are predominantly sensory in nature.

Section 3 Nerve and Muscle Disorders

446 Peripheral Neuropathy

Anthony A. Amato, Richard J. Barohn

Patient Complaint: ? Neuropathy

History and examination compatible with neuropathy?

Mononeuropathy Mononeuropathy multiplex Polyneuropathy Evaluation of other

 disorder or

 reassurance and

follow-up

EDx

Is the lesion axonal

 or demyelinating?

Is entrapment or

 compression present?

Is a contributing systemic

 disorder present?

Axonal Demyelinating

 with focal

 conduction block

Axonal Demyelinating

Consider

 vasculitis or

 other multifocal

 process

Consider

 multifocal

 form of

 CIDP

Subacute

 course (months)

Chronic

 course (years) Uniform slowing,

 chronic

Nonuniform slowing,

conduction block

Decision on need

 for surgery (nerve repair,

 transposition, or release

 procedure)

Possible

 nerve

 biopsy Test for paraprotein,

 HIV, Lyme disease

Review history for toxins;

 test for associated

systemic disease or

 intoxication

Test for paraprotein,

 if negative

Review family

 history; examine

family members;

 genetic testing

If chronic or

 subacute: CIDP

If acute: GBS

Treatment appropriate

 for specific diagnosis If tests are

 negative, consider

 treatment for

 CIDP

Treatment appropriate

 for specific diagnosis

Genetic counseling if appropriate

Treatment

 for CIDP;

 see Ch. 447

IVIg or

 plasmapheresis;

 supportive

 care including

 respiratory assistance

EDx EDx

Yes No

FIGURE 446-1 Approach to the evaluation of peripheral neuropathies. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; EDx, electrodiagnostic; GBS,

Guillain-Barré syndrome; IVIg, intravenous immunoglobulin.

3481Peripheral Neuropathy CHAPTER 446

2. What Is the Distribution of Weakness? Delineating the

pattern of weakness, if present, is essential for diagnosis, and in this

regard, two additional questions should be answered: (1) Does the

weakness only involve the distal extremity, or is it both proximal and

distal? and (2) Is the weakness focal and asymmetric, or is it symmetric? Symmetric proximal and distal weakness is the hallmark of

acquired immune demyelinating polyneuropathies, both the acute

form (Guillain-Barré syndrome [GBS]) and the chronic form (chronic

inflammatory demyelinating polyneuropathy [CIDP]) (Chap. 447).

The importance of finding symmetric proximal and distal weakness in

a patient who presents with both motor and sensory symptoms cannot

be overemphasized because this identifies the important subset of

patients who may have a treatable acquired demyelinating neuropathic

disorder (i.e., GBS or CIDP).

Findings of an asymmetric or multifocal pattern of weakness narrow

the differential diagnosis. Some neuropathic disorders may present

with unilateral extremity weakness. In the absence of sensory symptoms and signs, such weakness evolving over weeks or months would

be worrisome for motor neuron disease (e.g., amyotrophic lateral sclerosis [ALS]), but it would be important to exclude multifocal motor

neuropathy that may be treatable (Chap. 447). In a patient presenting

with asymmetric subacute or acute sensory and motor symptoms and

signs, radiculopathies, plexopathies, compressive mononeuropathies,

or multiple mononeuropathies (e.g., mononeuropathy multiplex) must

be considered.

ALS can produce prominent neck extensor weakness (head drop),

tongue and pharyngeal weakness (dysarthria and dysphagia), or

shortness of breath. These focal symmetric weakness patterns can

also be seen in neuromuscular junction disorders (myasthenia gravis,

Lambert-Eaton myasthenic syndrome [LEMS] [Chap. 448]) and some

myopathies, particularly isolated neck extensor myopathy (Chap. 449).

3. What Is the Nature of the Sensory Involvement? The

patient may have loss of sensation (numbness), altered sensation to

touch (hyperpathia or allodynia), or uncomfortable spontaneous sensations (tingling, burning, or aching) (Chap. 25). Neuropathic pain can

be burning, dull, and poorly localized (protopathic pain), presumably

transmitted by polymodal C nociceptor fibers, or sharp and lancinating

TABLE 446-1 Approach to Neuropathic Disorders:

Seven Key Questions

1. What systems are involved?

• Motor, sensory, autonomic, or combinations

2. What is the distribution of weakness?

• Only distal versus proximal and distal

• Focal/asymmetric versus symmetric

3. What is the nature of the sensory involvement?

• Temperature loss or burning or stabbing pain (e.g., small fiber)

• Vibratory or proprioceptive loss (e.g., large fiber)

4. Is there evidence of upper motor neuron involvement?

• Without sensory loss

• With sensory loss

5. What is the temporal evolution?

• Acute (days to 4 weeks)

• Subacute (4–8 weeks)

• Chronic (>8 weeks)

• Monophasic, progressive, or relapsing-remitting

6. Is there evidence for a hereditary neuropathy?

• Family history of neuropathy

• Lack of sensory symptoms despite sensory signs

7. Are there any associated medical conditions?

• Cancer, diabetes mellitus, connective tissue disease or other autoimmune

diseases, infection (e.g., HIV, Lyme disease, leprosy)

• Medications including over-the-counter drugs that may cause a toxic

neuropathy

• Preceding events, drugs, toxins

TABLE 446-2 Patterns of Neuropathic Disorders

Pattern 1: Symmetric proximal and distal weakness with sensory loss

Consider: inflammatory demyelinating polyneuropathy (GBS and CIDP)

Pattern 2: Symmetric distal sensory loss with or without distal weakness

 Consider: cryptogenic or idiopathic sensory polyneuropathy (CSPN), diabetes

mellitus and other metabolic disorders, drugs, toxins, familial (HSAN), CMT,

amyloidosis, and others

Pattern 3: Asymmetric distal weakness with sensory loss

With involvement of multiple nerves

 Consider: multifocal CIDP, vasculitis, cryoglobulinemia, amyloidosis, sarcoid,

infectious (leprosy, Lyme, hepatitis B, C, or E, HIV, CMV), HNPP, tumor infiltration

With involvement of single nerves/regions

 Consider: may be any of the above but also could be compressive

mononeuropathy, plexopathy, or radiculopathy

Pattern 4: Asymmetric proximal and distal weakness with sensory loss

 Consider: polyradiculopathy or plexopathy due to diabetes mellitus, meningeal

carcinomatosis or lymphomatosis, sarcoid, amyloid, hereditary plexopathy (HNPP,

HNA), idiopathic

Pattern 5: Asymmetric distal weakness without sensory loss

With upper motor neuron findings

 Consider: motor neuron disease

Without upper motor neuron findings

 Consider: progressive muscular atrophy, juvenile monomelic amyotrophy

(Hirayama’s disease), multifocal motor neuropathy, multifocal acquired motor

axonopathy

Pattern 6: Symmetric sensory loss and distal areflexia with upper motor neuron

findings

 Consider: vitamin B12, vitamin E, and copper deficiency with combined system

degeneration with peripheral neuropathy, chronic liver disease, hereditary

leukodystrophies (e.g., adrenomyeloneuropathy) HSP-plus

Pattern 7: Symmetric weakness without sensory loss

With proximal and distal weakness

 Consider: SMA

With distal weakness

 Consider: hereditary motor neuropathy (“distal” SMA) or atypical CMT

Pattern 8: Focal midline proximal symmetric weakness

Neck extensor weakness

 Consider: ALS

Bulbar weakness

 Consider: ALS/PLS, isolated bulbar ALS (IBALS), Kennedy’s syndrome (X-linked,

bulbospinal SMA), bulbar presentation GBS

Diaphragm weakness (SOB)

 Consider: ALS

Pattern 9: Asymmetric proprioceptive sensory loss without weakness

Consider causes of a sensory neuronopathy (ganglionopathy):

Cancer (paraneoplastic)

Sjögren’s syndrome

Idiopathic sensory neuronopathy (possible GBS variant)

Cisplatin and other chemotherapeutic agents

Vitamin B6

 toxicity

HIV-related sensory neuronopathy

Pattern 10: Autonomic symptoms and signs

Consider neuropathies associated with prominent autonomic dysfunction:

Hereditary sensory and autonomic neuropathy

Amyloidosis (familial and acquired)

Diabetes mellitus

GBS

Idiopathic pandysautonomia (may be a variant of GBS)

Porphyria

HIV-related autonomic neuropathy

Vincristine and other chemotherapeutic agents

Abbreviations: ALS, amyotrophic lateral sclerosis; CIDP, chronic inflammatory

demyelinating polyneuropathy; CMT, Charcot-Marie-Tooth disease; CMV,

cytomegalovirus; GBS, Guillain-Barré syndrome; HIV, human immunodeficiency

virus; HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropathy with

liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy;

HSP-plus, hereditary spastic paraplegia plus neuropathy; PLS, primary lateral

sclerosis; SMA, spinal muscular atrophy; SOB, shortness of breath.

3482 PART 13 Neurologic Disorders

(epicritic pain), relayed by A-delta fibers. If pain and temperature perception are lost, while vibratory and position sense are preserved along

with muscle strength, deep tendon reflexes, and normal nerve conduction studies (NCS), a small-fiber neuropathy is likely. The most likely

causes of small-fiber neuropathies, when one is identified, are diabetes

mellitus (DM) or glucose intolerance. Amyloid neuropathy should be

considered as well in such cases, but most of these small-fiber neuropathies remain idiopathic despite extensive evaluation.

Severe proprioceptive loss also narrows the differential diagnosis.

Affected patients will note imbalance, especially in the dark. A neurologic examination revealing a dramatic loss of proprioception with

vibration loss and normal strength should alert the clinician to consider a sensory neuronopathy/ganglionopathy (Pattern 9, Table 446-2).

In particular, if this loss is asymmetric or affects the arms more than

the legs, this pattern suggests a non-length-dependent process as seen

in sensory neuronopathies.

4. Is There Evidence of Upper Motor Neuron Involvement?

If the patient presents with symmetric distal sensory symptoms and

signs suggestive of a distal sensory neuropathy, but there is additional

evidence of symmetric upper motor neuron involvement (Chap. 24),

the physician should consider a combined system degeneration with

neuropathy. The most common cause for this pattern is vitamin B12

deficiency, but other etiologies should also be considered (e.g., copper

deficiency, human immunodeficiency virus [HIV] infection, severe

hepatic disease, adrenomyeloneuropathy [AMN]), and hereditary

spastic paraplegia plus a neuropathy.

5. What Is the Temporal Evolution? It is important to determine the onset, duration, and evolution of symptoms and signs. Does

the disease have an acute (days to 4 weeks), subacute (4–8 weeks), or

chronic (>8 weeks) course? Is the course monophasic, progressive, or

relapsing? Most neuropathies are insidious and slowly progressive in

nature. Neuropathies with acute and subacute presentations include

GBS, vasculitis, and radiculopathies related to diabetes or Lyme disease. A relapsing course can be present in CIDP and porphyria.

6. Is There Evidence for a Hereditary Neuropathy? In

patients with slowly progressive distal weakness over many years

with few sensory symptoms yet significant sensory deficits on clinical

examination, the clinician should consider a hereditary neuropathy

(e.g., Charcot-Marie-Tooth disease [CMT]). On examination, the feet

may show high or flat arches or hammer toes, and scoliosis may be

present. In suspected cases, it may be necessary to perform neurologic

and electrophysiologic studies on family members in addition to the

patient.

7. Does the Patient Have Any Other Medical Conditions? It

is important to inquire about associated medical conditions (e.g.,

DM, systemic lupus erythematosus [SLE]); preceding or concurrent

infections (e.g. diarrheal illness preceding GBS); surgeries (e.g., gastric

bypass and nutritional neuropathies); medications (toxic neuropathy),

including over-the-counter vitamin preparations (B6

); alcohol; dietary

habits; and use of dentures (e.g., fixatives contain zinc that can lead to

copper deficiency).

■ PATTERN RECOGNITION APPROACH TO

NEUROPATHIC DISORDERS

Based on the answers to the seven key questions, neuropathic disorders can be classified into several patterns based on the distribution or

pattern of sensory, motor, and autonomic involvement (Table 446-2).

Each pattern has a limited differential diagnosis, and information from

laboratory studies usually permits a final diagnosis to be established.

■ ELECTRODIAGNOSTIC STUDIES

The electrodiagnostic (EDx) evaluation of patients with a suspected

peripheral neuropathy consists of NCS and needle electromyography

(EMG). In addition, studies of autonomic function can be valuable. The

electrophysiologic data can confirm whether the neuropathic disorder

is a mononeuropathy, multiple mononeuropathy (mononeuropathy

multiplex), radiculopathy, plexopathy, or generalized polyneuropathy.

Similarly, EDx evaluation can ascertain whether the process involves

only sensory fibers, motor fibers, autonomic fibers, or a combination

of these. Finally, the electrophysiologic data can help distinguish

axonopathies from myelinopathies as well as axonal degeneration secondary to ganglionopathies from the more common length-dependent

axonopathies.

NCS are most helpful in classifying a neuropathy as due to axonal

degeneration or segmental demyelination (Table 446-3). In general,

low-amplitude potentials with relatively preserved distal latencies,

conduction velocities, and late potentials, along with fibrillations on

needle EMG, suggest an axonal neuropathy. On the other hand, slow

conduction velocities, prolonged distal latencies and late potentials,

relatively preserved amplitudes, and the absence of fibrillations on

needle EMG imply a primary demyelinating neuropathy. The presence

of nonuniform slowing of conduction velocity, conduction block, or

temporal dispersion further suggests an acquired demyelinating neuropathy (e.g., GBS or CIDP) as opposed to a hereditary demyelinating

neuropathy (e.g., CMT type 1).

Autonomic studies are used to assess small myelinated (A-delta)

or unmyelinated (C) nerve fiber involvement. Such testing includes

heart rate response to deep breathing, heart rate, and blood pressure

response to both the Valsalva maneuver and tilt-table testing and quantitative sudomotor axon reflex testing (Chap. 440). These studies are

particularly useful in patients who have pure small-fiber neuropathy or

autonomic neuropathy in which routine NCS are normal.

■ OTHER IMPORTANT LABORATORY

INFORMATION

In patients with generalized symmetric peripheral neuropathy, a standard laboratory evaluation should include a complete blood count,

basic chemistries including serum electrolytes and tests of renal and

hepatic function, fasting blood glucose (FBS), hemoglobin (Hb) A1c,

urinalysis, thyroid function tests, B12, folate, erythrocyte sedimentation

rate (ESR), rheumatoid factor, antinuclear antibodies (ANA), serum

protein electrophoresis (SPEP) and immunoelectrophoresis or immunofixation, and urine for Bence Jones protein. Quantification of the

TABLE 446-3 Electrophysiologic Features: Axonal Degeneration versus

Segmental Demyelination

AXONAL DEGENERATION

SEGMENTAL

DEMYELINATION

Motor Nerve Conduction Studies

CMAP amplitude Decreased Normal (except with CB

or distal dispersion)

Distal latency Normal Prolonged

Conduction velocity Normal Slow

Conduction block Absent Present

Temporal dispersion Absent Present

F wave Normal or absent Prolonged or absent

H reflex Normal or absent Prolonged or absent

Sensory Nerve Conduction Studies

SNAP amplitude Decreased Normal or decreased

Distal latency Normal Prolonged

Conduction velocity Normal Slow

Needle EMG

Spontaneous activity

Fibrillations Present Absent

Fasciculations Present Absent

Motor unit potentials

Recruitment Decreased Decreased

Morphology Long duration, large

amplitude, polyphasic

(if there is reinnervation)

Normal

Abbreviations: CB, conduction block; CMAP, compound motor action potential;

EMG, electromyography; SNAP, sensory nerve action potential.

3483Peripheral Neuropathy CHAPTER 446

concentration of serum-free light chains and the kappa/lambda ratio is

more sensitive than SPEP, immunoelectrophoresis, or immunofixation

to detect a monoclonal gammopathy and therefore should be done if

amyloidosis is suspected. A skeletal survey should be performed in

patients with acquired demyelinating neuropathies and M-spikes to

look for osteosclerotic or lytic lesions. Patients with monoclonal gammopathy should also be referred to a hematologist for consideration

of a bone marrow biopsy. An oral glucose tolerance test is indicated in

patients with painful sensory neuropathies even if FBS and HbA1c are

normal, as the test is abnormal in about one-third of such patients. In

addition to the above tests, patients with a mononeuropathy multiplex

pattern of involvement should have a vasculitis workup, including

antineutrophil cytoplasmic antibodies (ANCAs), cryoglobulins, hepatitis serology, Western blot for Lyme disease, HIV, and occasionally a

cytomegalovirus (CMV) titer.

There are many autoantibody panels (various antiganglioside antibodies) marketed for screening routine neuropathy patients for a treatable condition. These autoantibodies have no proven clinical utility

or added benefit beyond the information obtained from a complete

clinical examination and detailed EDx. A heavy metal screen is also

not necessary as a screening procedure, unless there is a history of

possible exposure or suggestive features on examination (e.g., severe

painful sensorimotor and autonomic neuropathy and alopecia—

thallium; severe painful sensorimotor neuropathy with or without

gastrointestinal [GI] disturbance and Mee’s lines—arsenic; wrist or

finger extensor weakness and anemia with basophilic stippling of red

blood cells—lead).

In patients with suspected GBS or CIDP, a lumbar puncture is

indicated to look for an elevated cerebrospinal fluid (CSF) protein. In

idiopathic cases of GBS and CIDP, CSF pleocytosis is usually absent.

If cells are present, one should consider HIV infection, Lyme disease,

sarcoidosis, or lymphomatous or leukemic infiltration of nerve roots.

Recently, serum IgG4 antibodies to neurofascin and contactin-2 have

been discovered in CIDP with severe sensory ataxia, tremor, and distal

weakness (Chap. 447). These cases are difficult to treat with standard

immunotherapies but may respond to rituximab. Some patients with

GBS and CIDP have abnormal liver function tests. In these cases,

it is important to also check for hepatitis B and C, HIV, CMV, and

Epstein-Barr virus (EBV) infection. In patients with an axonal

GBS (by EMG/NCS) or those with a suspicious coinciding history

(e.g., unexplained abdominal pain, psychiatric illness, significant autonomic dysfunction), it is reasonable to screen for porphyria.

In patients with a severe sensory ataxia, a sensory ganglionopathy

or neuronopathy should be considered. The most common causes of

sensory ganglionopathies are Sjögren’s syndrome (Chap. 361) and a

paraneoplastic neuropathy (Chap. 94). Neuropathy can be the initial

manifestation of Sjögren’s syndrome. Thus, one should always inquire

about dry eyes and mouth in patients with sensory signs and symptoms.

Further, some patients can manifest sicca complex without other manifestations of Sjögren’s syndrome. Thus, patients with sensory ataxia

should be tested for antibodies to SS-A/Ro and SS-B/La, in addition to

the routine ANA. To evaluate a possible paraneoplastic sensory ganglionopathy, antineuronal nuclear antibodies (e.g., anti-Hu antibodies)

should be obtained. These antibodies are most commonly seen in

patients with small-cell carcinoma of the lung but are also present with

breast, ovarian, lymphoma, and other cancers. Importantly, the paraneoplastic neuropathy can precede the detection of the cancer, and detection of these autoantibodies should lead to a search for malignancy.

■ NERVE BIOPSIES

Nerve biopsies are now rarely performed in the evaluation of neuropathies. The primary indication for nerve biopsy is suspicion for amyloid

neuropathy or vasculitis. In most instances, the abnormalities present

on biopsies do not help distinguish one form of peripheral neuropathy

from another (beyond what is already apparent by clinical examination

and the NCS). Nerve biopsies should only be performed when the NCS

are abnormal. The sural nerve is most commonly biopsied because

it is a pure sensory nerve and biopsy will not result in loss of motor

function. In suspected vasculitis, a combination biopsy of a superficial

peroneal nerve (pure sensory) and the underlying peroneus brevis

muscle obtained from a single small incision increases the diagnostic

yield. Tissue can be analyzed to assess for evidence of inflammation,

vasculitis, or amyloid deposition. Semithin plastic sections, teased

fiber preparations, and electron microscopy are used to assess the

morphology of the nerve fibers and to distinguish axonopathies from

myelinopathies.

■ SKIN BIOPSIES

Skin biopsies are sometimes used to diagnose a small-fiber neuropathy.

Following a punch biopsy of the skin in the distal lower extremity,

immunologic staining can be used to measure the density of small

unmyelinated fibers. The density of these nerve fibers is reduced in

patients with small-fiber neuropathies in whom NCS and routine nerve

biopsies are often normal. This technique may allow for an objective

measurement in patients with mainly subjective symptoms. However,

it often adds little to what one already knows from the clinical examination and EDx.

SPECIFIC DISORDERS

■ HEREDITARY NEUROPATHIES

CMT disease is the most common type of hereditary neuropathy

(Pattern 2, Table 446-2). Rather than one disease, CMT is a syndrome

of many genetically distinct disorders (Table 446-4). The various

subtypes of CMT are classified according to the nerve conduction

velocities (NCVs) and predominant pathology (e.g., demyelination

or axonal degeneration), inheritance pattern (autosomal dominant,

recessive, or X-linked), and the specific mutated genes. Type 1 CMT

(or CMT1) refers to inherited demyelinating sensorimotor neuropathies, whereas the axonal sensory neuropathies are classified as CMT2.

By definition, motor conduction velocities in the arms are slowed to

<38 m/s in CMT1 and are >38 m/s in CMT2. However, most cases of

CMT1 actually have motor NCVs between 20 and 25 m/s. CMT1 and

CMT2 usually begin in childhood or early adult life; however, onset

later in life can occur, particularly in CMT2. Both are inherited in an

autosomal dominant fashion, with a few exceptions. CMT3 is an autosomal dominant neuropathy that appears in infancy and is associated

with severe demyelination or hypomyelination. CMT4 is an autosomal

recessive neuropathy that typically begins in childhood or early adult

life. There are no medical therapies for any of the CMTs, but physical

and occupational therapy can be beneficial, as can bracing (e.g., anklefoot orthotics for foot drop) and other orthotic devices.

■ CMT1

CMT1 is the most common form of hereditary neuropathy. Affected

individuals usually present in the first to third decade of life with distal

leg weakness (e.g., foot drop), although patients may remain asymptomatic even late in life. People with CMT generally do not complain

of numbness or tingling, which can be helpful in distinguishing CMT

from acquired forms of neuropathy in which sensory symptoms usually predominate. Although usually asymptomatic, reduced sensation

to all modalities is apparent on examination. Muscle stretch reflexes

are unobtainable or reduced throughout. There is often atrophy of the

muscles below the knee (particularly the anterior compartment), leading to so-called inverted champagne bottle legs.

Motor NCVs are generally in the 20–25 m/s range. Nerve biopsies

usually are not performed on patients suspected of having CMT1,

because the diagnosis usually can be made by less invasive testing (e.g.,

NCS and genetic studies). However, when done, the biopsies reveal

reduced numbers of myelinated nerve fibers with a predilection for loss

of large-diameter fibers and Schwann cell proliferation around thinly

or demyelinated fibers, forming so-called onion bulbs.

CMT1A is the most common subtype of CMT1, representing 70% of

cases, and is caused by a 1.5-megabase (Mb) duplication within chromosome 17p11.2-12 encoding the gene for peripheral myelin protein-22

(PMP-22). This results in patients having three copies of the PMP-22

gene rather than two. This protein accounts for 2–5% of myelin

protein and is expressed in compact regions of the peripheral myelin

sheath. Approximately 20% of patients with CMT1 have CMT1B,

3484 PART 13 Neurologic Disorders

TABLE 446-4 Classification of Charcot-Marie-Tooth Disease and Related Neuropathies

NAME INHERITANCE GENE LOCATION GENE PRODUCT

CMT1

CMT1A AD 17p11.2 PMP-22 (usually duplication of gene)

CMT1B AD 1q21-23 MPZ

CMT1C AD 16p13.1-p12.3 LITAF

CMT1D AD 10q21.1-22.1 ERG2

CMT1E (with deafness) AD 17p11.2 Point mutations in PMP-22 gene

CMT1F AD 8p13-21 Neurofilament light chain

CMT1G AD 8q21 PMP2

CMT1X X-linked dominant Xq13 Connexin-32

HNPP AD 17p11.2 PMP-22

1q21-23 MPZ

CMT dominant-intermediate (CMTDI)

CMT-DIA AD 10q24.1-25.1 ?

CMT-DIB AD 19.p12-13.2 Dynamin 2

CMT-DIC AD 1p35 YARS

CMT-DID

CMT-DIE

CMT-DIF

CMT-DIG

AD

AD

AD

AD

1q22

14q32.33

3q26

8p31

MPZ

IFN-2

GNB4

NEFL

CMT recessive-intermediate (CMT-RI)

CMT-RIA

CMT-RIB

CMT-RIC

CMT-RI D

AR

AR

AR

AR

8q21.1

6q23

1p36

12q24

GDAP1

KARS5

PLEKHG5

COX6A1

CMT2

CMT2A2 (allelic to HMSN VI with optic atrophy) AD 1p36.2 MFN2

CMT2B AD 3q13-q22 RAB7

CMT2B1 (allelic to LGMD 1B) AR 1q21.2 Lamin A/C

CMT2B2 AR and AD 19q13 MED25 for AR; unknown for AD

CMT2C (with vocal cord and diaphragm paralysis) AD 12q23-24 TRPV4

CMT2D (allelic to distal SMA5) AD 7p14 Glycine tRNA synthetase

CMT2E (allelic to CMT 1F) AD 8p21 Neurofilament light chain

CMT2F AD 7q11-q21 Heat-shock 27-kDa protein-1

CMT2G AD 9q31.3-34.2 LRSAM1

CMT2I (allelic to CMT1B) AD 1q22 MPZ

CMT2J AD 1q22 MPZ

CMT2H, CMT2K (allelic to CMT4A) AD 8q13-q21 GDAP1

 CMT2L (allelic to distal hereditary motor

neuropathy type 2)

AD 12q24 Heat-shock protein 8

CMT2M AD 16q22 Dynamin-2

CMT2N AD 16q22.1 AARS

CMT2O AD 14q32.31 DYNC1H1

CMT2P AD 9q31.3-34.2 LRSAM1

CMT2P-Okinawa (HSMN2P) AD 3q13-q14 TFG

CMT2Q

CMT2U

CMT2V

CMT2W

CMT2Y

CMT2Z

CMT2X

AD

AD

AD

AD

AD

AD

X-linked

10p14

12q13

17q11

5q31

9p13

22q12

Xq22-24

DHTKD1

MARS

NAGLU

HARS

VCP

MRC2

PRPS1

CMT3 AD 17p11.2 PMP-22

 (Dejerine-Sottas disease, congenital

hypomyelinating neuropathy)

AD 1q21-23 MPZ

AR 10q21.1-22.1 ERG2

AR 19q13 Periaxon

(Continued)

3485Peripheral Neuropathy CHAPTER 446

caused by mutations in the myelin protein zero (MPZ). CMT1B is

for the most part clinically, electrophysiologically, and histologically

indistinguishable from CMT1A. MPZ is an integral myelin protein and

accounts for more than half of the myelin protein in peripheral nerves.

Other forms of CMT1 are much less common and also indistinguishable from one another clinically and electrophysiologically.

■ CMT2

CMT2 occurs approximately half as frequently as CMT1, and CMT2

tends to present later in life. Affected individuals usually become symptomatic in the second decade; some cases present earlier in childhood,

whereas others remain asymptomatic into late adult life. Clinically, CMT2

is for the most part indistinguishable from CMT1. NCS are helpful in this

regard; in contrast to CMT1, the velocities are normal or only slightly

slowed. The most common cause of CMT2 is a mutation in the gene for

mitofusin 2 (MFN2), which accounts for ~20–30% of CMT2 cases overall.

MFN2 localizes to the outer mitochondrial membrane, where it regulates

the mitochondrial network architecture by participating in mitochondrial

fusion. The other genes associated with CMT2 are much less common.

■ CMTDI

In dominant-intermediate CMTs (CMTDIs), the NCVs are faster than

usually seen in CMT1 (e.g., >38 m/s) but slower than in CMT2.

■ CMT3

CMT3 was originally described by Dejerine and Sottas as a hereditary

demyelinating sensorimotor polyneuropathy presenting in infancy or

early childhood. Affected children are severely weak. Motor NCVs are

markedly slowed, typically ≤5–10 m/s. Most cases of CMT3 are caused

by point mutations in the genes for PMP-22, MPZ, or ERG-2, which

are also the genes responsible for CMT1.

■ CMT4

CMT4 is extremely rare and is characterized by a severe, childhoodonset sensorimotor polyneuropathy that is usually inherited in an

autosomal recessive fashion. Electrophysiologic and histologic evaluations can show demyelinating or axonal features. CMT4 is genetically

heterogeneous (Table 446-4).

■ CMT1X

CMT1X is an X-linked dominant disorder with clinical features similar

to CMT1 and CMT2, except that the neuropathy is much more severe

in males than in females. CMT1X accounts for ~10–15% of CMT

overall. Males usually present in the first two decades of life with atrophy and weakness of the distal arms and legs, areflexia, pes cavus, and

hammer toes. Obligate female carriers are frequently asymptomatic

TABLE 446-4 Classification of Charcot-Marie-Tooth Disease and Related Neuropathies

NAME INHERITANCE GENE LOCATION GENE PRODUCT

CMT4

CMT4A AR 8q13-21.1 GDAP1

CMT4B1 AR 11q23 MTMR2

CMT4B2 AR 11p15 MTMR13

CMT4C AR 5q23-33 SH3TC2

CMT4D (HMSN-Lom) AR 8q24 NDRG1

CMT4E (congenital hypomyelinating neuropathy) AR Multiple Includes PMP-22, MPZ, and ERG-2

CMT4F AR 19q13.1-13.3 Periaxin

CMT4G AR 10q23.2 HK1

CMT4H AR 12q12-q13 Frabin

CMT4J

CMT4K

AR

AR

6q21

9q34

FIG4

SURF1

HNA AD 17q24 SEPT9

HSAN1A AD 9q22 SPTLC1

HSAN1B AD 3q21 RAB7

HSAN1C AD 14q24.3 SPTLC2

HSAN1D AD 14q21.3 ATL1

HSAN1E AD 19p13.2 DNMT1

HSAN2A AR 12p13.33 PRKWNK1

HSAN2B AR 5p15.1 FAM134B

HSAN2C AR 12q13.13 KIF1A

HSAN2D AR 2q24.3 SCN9A

HSAN3A AR 9q21 IKAP

HSAN3B AR 6p12.1 Dystonin

HSAN4 AR 3q trkA/NGF receptor

HSAN5 AD or AR 1p11.2-p13.2

2q24.3

3p22.2

NGFb

SCN9A

SCN11A

HSAN6 AR 6p12.1 Dystonin

Abbreviations: AARS, alanyl-tRNA synthetase; AD, autosomal dominant; AR, autosomal recessive; ATL, atlastin; CMT, Charcot-Marie-Tooth; DNMT1, DNA methyltransferase 1;

DYNC1HI, cytoplasmic dynein 1 heavy chain 1; ERG2, early growth response-2 protein; FAM134B, family with sequence similarity 134, member B; FIG4, FDG1-related F

actin-binding protein; GDAP1, ganglioside-induced differentiation-associated protein-1; HK1, hexokinase 1; HMSN-P, hereditary motor and sensory neuropathy proximal;

HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy; IFN2, inverted

formin-2; IKAP, k

B kinase complex-associated protein; LGMD, limb girdle muscular dystrophy; LITAF, lipopolysaccharide-induced tumor necrosis factor α factor; LRSAM1, E3

ubiquitin-protein ligase; MED25, mediator 25; MFN2, mitochondrial fusion protein mitofusin 2 gene; MPZ, myelin protein zero protein; MTMR2, myotubularin-related protein-2;

NDRG1, N-myc downstream regulated 1; PMP-22, peripheral myelin protein-22; PRKWNK1, protein kinase, lysine deficient 1; PRPS1, phosphoribosylpyrophosphate

synthetase 1; RAB7, Ras-related protein 7; SEPT9, Septin 9; SH3TC2, SH3 domain and tetratricopeptide repeats 2; SMA, spinal muscular atrophy; SPTLC, serine

palmitoyltransferase long-chain base; TFG, TRK-fused gene; TrkA/NGF, tyrosine kinase A/nerve growth factor; tRNA, transfer ribonucleic acid; TRPV4, transient receptor

potential cation channel, subfamily V, member 4; WNK1, WNK lysine deficient; YARS, tyrosyl-tRNA synthetase.

Source: Modified from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill, 2016, Table 11-1, pp 265–266.

(Continued)

3486 PART 13 Neurologic Disorders

but can develop signs and symptoms of CMT. Onset in females is

usually after the second decade of life, and the neuropathy is milder in

severity.

NCS reveal features of both demyelination and axonal degeneration.

In males, motor NCVs in the arms and legs are moderately slowed

(in the low to mid 30-m/s range). About 50% of males with CMT1X

have motor NCVs between 15 and 35 m/s with ~80% of these falling

between 25 and 35 m/s (intermediate slowing). In contrast, ~80% of

females with CMT1X have NCVs in the normal range and 20% have

NCVs in the intermediate range. CMT1X is caused by mutations in the

connexin-32 gene. Connexins are gap junction structural proteins that

are important in cell-to-cell communication.

Hereditary Neuropathy with Liability to Pressure Palsies

(HNPP) HNPP is an autosomal dominant disorder related to

CMT1A. While CMT1A is usually associated with a 1.5-Mb duplication in chromosome 17p11.2 that results in an extra copy of PMP-22

gene, HNPP is caused by inheritance of the chromosome with the

corresponding 1.5-Mb deletion of this segment, and thus, affected

individuals have only one copy of the PMP-22 gene. Patients usually

manifest in the second or third decade of life with painless numbness

and weakness in the distribution of single peripheral nerves, although

multiple mononeuropathies can occur (Pattern 3, Table 446-2).

Symptomatic mononeuropathy or multiple mononeuropathies are

often precipitated by trivial compression of nerve(s) as can occur

with wearing a backpack, leaning on the elbows, or crossing one’s

legs for even a short period of time. These pressure-related mononeuropathies may take weeks or months to resolve. In addition, some

affected individuals manifest with a progressive or relapsing, generalized and symmetric, sensorimotor peripheral neuropathy that

resembles CMT.

Hereditary Neuralgic Amyotrophy (HNA) HNA is an autosomal dominant disorder characterized by recurrent attacks of pain,

weakness, and sensory loss in the distribution of the brachial plexus

often beginning in childhood (Pattern 4, Table 446-2). These attacks

are similar to those seen with idiopathic brachial plexitis (see below).

Attacks may occur in the postpartum period, following surgery, or

at other times of stress. Most patients recover over several weeks or

months. Slightly dysmorphic features, including hypotelorism, epicanthal folds, cleft palate, syndactyly, micrognathia, and facial asymmetry,

are evident in some individuals. EDx demonstrate an axonal process.

HNA is genetically heterogeneous but can be caused by mutations in

septin 9 (SEPT9). Septins may be important in formation of the neuronal cytoskeleton and have a role in cell division, but it is not known

how mutations in SEPT9 lead to HNA.

Hereditary Sensory and Autonomic Neuropathy (HSAN)

The HSANs are a very rare group of hereditary neuropathies in which

sensory and autonomic dysfunction predominates over muscle weakness, unlike CMT, in which motor findings are most prominent (Pattern 2,

Table 446-2; Table 446-4). Nevertheless, affected individuals can develop

motor weakness, and there can be overlap with CMT. There are no medical therapies available to treat these neuropathies, other than prevention and treatment of mutilating skin and bone lesions.

Of the HSANs, only HSAN1 typically presents in adults. HSAN1

is the most common of the HSANs and is inherited in an autosomal

dominant fashion. Affected individuals usually manifest in the second through fourth decades of life. HSAN1 is associated with the

degeneration of small myelinated and unmyelinated nerve fibers

leading to severe loss of pain and temperature sensation, deep dermal ulcerations, recurrent osteomyelitis, Charcot joints, bone loss,

gross foot and hand deformities, and amputated digits. Although

most people with HSAN1 do not complain of numbness, they often

describe burning, aching, or lancinating pains. Autonomic neuropathy is not a prominent feature, but bladder dysfunction and reduced

sweating in the feet may occur. HSAN1A, which is most common,

is caused by mutations in the serine palmitoyltransferase long-chain

base 1 (SPTLC1) gene.

OTHER HEREDITARY NEUROPATHIES

(TABLE 446-5)

■ FABRY’S DISEASE

Fabry’s disease (angiokeratoma corporis diffusum) is an X-linked

dominant disorder. Although men are more commonly and severely

affected, women can also manifest symptoms and signs of the disease.

Angiokeratomas are reddish-purple maculopapular lesions that are

usually found around the umbilicus, scrotum, inguinal region, and

perineum. Burning or lancinating pain in the hands and feet often

develops in males in late childhood or early adult life (Pattern 2,

Table 446-2). However, the neuropathy is usually overshadowed by

complications arising from an associated premature atherosclerosis

(e.g., hypertension, renal failure, cardiac disease, and stroke) that often

lead to death by the fifth decade of life. Some patients also manifest

primarily with a dilated cardiomyopathy.

Fabry’s disease is caused by mutations in the α-galactosidase gene

that leads to the accumulation of ceramide trihexoside in nerves

and blood vessels. A decrease in α-galactosidase activity is evident

in leukocytes and cultured fibroblasts. Glycolipid granules may be

appreciated in ganglion cells of the peripheral and sympathetic nervous

systems and in perineurial cells. Enzyme replacement therapy with

α-galactosidase B can improve the neuropathy if patients are treated

early, before irreversible nerve fiber loss develops.

■ ADRENOLEUKODYSTROPHY/

ADRENOMYELONEUROPATHY

Adrenoleukodystrophy (ALD) and AMN are allelic X-linked dominant

disorders caused by mutations in the peroxisomal transmembrane adenosine triphosphate-binding cassette (ABC) transporter gene. Patients

with ALD manifest with central nervous system (CNS) abnormalities.

However, ~30% of patients with mutations in this gene present with the

AMN phenotype that typically manifests in the third to fifth decade

of life as mild to moderate peripheral neuropathy combined with

TABLE 446-5 Rare Hereditary Neuropathies

Hereditary Disorders of Lipid Metabolism

Metachromatic leukodystrophy

Krabbe’s disease (globoid cell leukodystrophy)

Fabry’s disease

Adrenoleukodystrophy/adrenomyeloneuropathy

Refsum’s disease

Tangier disease

Cerebrotendinous xanthomatosis

Hereditary Ataxias with Neuropathy

Friedreich’s ataxia

Vitamin E deficiency

Spinocerebellar ataxia

Abetalipoproteinemia (Bassen-Kornzweig disease)

Disorders of Defective DNA Repair

Ataxia-telangiectasia

Cockayne’s syndrome

Giant Axonal Neuropathy

Porphyria

Acute intermittent porphyria (AIP)

Hereditary coproporphyria (HCP)

Variegate porphyria (VP)

Familial Amyloid Polyneuropathy (FAP)

Transthyretin-related

Gelsolin-related

Apolipoprotein A1-related

Source: Modified from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed.

New York, McGraw-Hill, 2016, Table 12-1, p. 299.

3487Peripheral Neuropathy CHAPTER 446

progressive spastic paraplegia (Pattern 6, Table 446-2) (Chap. 442).

Rare patients present with an adult-onset spinocerebellar ataxia or only

with adrenal insufficiency.

EDx is suggestive of a primary axonopathy with secondary demyelination. Nerve biopsies demonstrate a loss of myelinated and unmyelinated nerve fibers with lamellar inclusions in the cytoplasm of

Schwann cells. Very-long-chain fatty acid (VLCFA) levels (C24, C25,

and C26) are increased in the urine. Laboratory evidence of adrenal

insufficiency is evident in approximately two-thirds of patients. The

diagnosis can be confirmed by genetic testing.

Adrenal insufficiency is managed by replacement therapy; however,

there is no proven effective therapy for the neurologic manifestations

of ALD/AMN. Diets low in VLCFAs and supplemented with Lorenzo’s

oil (erucic and oleic acids) reduce the levels of VLCFAs and increase

the levels of C22 in serum, fibroblasts, and liver; however, several large,

open-label trials of Lorenzo’s oil failed to demonstrate efficacy.

■ REFSUM’S DISEASE

Refsum’s disease can manifest in infancy to early adulthood with the

classic tetrad of (1) peripheral neuropathy, (2) retinitis pigmentosa,

(3) cerebellar ataxia, and (4) elevated CSF protein concentration.

Most affected individuals develop progressive distal sensory loss and

weakness in the legs leading to foot drop by their twenties (Pattern 2,

Table 446-2). Subsequently, the proximal leg and arm muscles may

become weak. Patients may also develop sensorineural hearing loss,

cardiac conduction abnormalities, ichthyosis, and anosmia.

Serum phytanic acid levels are elevated. Sensory and motor NCS

reveal reduced amplitudes, prolonged latencies, and slowed conduction

velocities. Nerve biopsy demonstrates a loss of myelinated nerve fibers,

with remaining axons often thinly myelinated and associated with

onion bulb formation.

Refsum’s disease is genetically heterogeneous but autosomal recessive in nature. Classical Refsum’s disease with childhood or early adult

onset is caused by mutations in the gene that encodes for phytanoylCoA α-hydroxylase (PAHX). Less commonly, mutations in the gene

encoding peroxin 7 receptor protein (PRX7) are responsible. These

mutations lead to the accumulation of phytanic acid in the central

and peripheral nervous systems. Treatment is removal of phytanic

precursors (phytols: fish oils, dairy products, and ruminant fats) from

the diet.

■ TANGIER DISEASE

Tangier disease is a rare autosomal recessive disorder that can present as (1) asymmetric multiple mononeuropathies, (2) a slowly

progressive symmetric polyneuropathy predominantly in the legs, or

(3) a pseudo-syringomyelia pattern with dissociated sensory loss

(i.e., abnormal pain/temperature perception but preserved position/

vibration in the arms [Chap. 442]). The tonsils may appear swollen

and yellowish-orange in color, and there may also be splenomegaly and

lymphadenopathy.

Tangier disease is caused by mutations in the ATP-binding cassette

transporter 1 (ABC1) gene, which leads to markedly reduced levels of

high-density lipoprotein (HDL) cholesterol levels, whereas triacylglycerol levels are increased. Nerve biopsies reveal axonal degeneration

with demyelination and remyelination. Electron microscopy demonstrates abnormal accumulation of lipid in Schwann cells, particularly

those encompassing unmyelinated and small myelinated nerves. There

is no specific treatment.

■ PORPHYRIA

Porphyria is a group of inherited disorders caused by defects in heme

biosynthesis (Chap. 416). Three forms of porphyria are associated

with peripheral neuropathy: acute intermittent porphyria (AIP),

hereditary coproporphyria (HCP), and variegate porphyria (VP). The

acute neurologic manifestations are similar in each, with the exception

that a photosensitive rash is seen with HCP and VP but not in AIP.

Attacks of porphyria can be precipitated by certain drugs (usually those

metabolized by the P450 system), hormonal changes (e.g., pregnancy,

menstrual cycle), and dietary restrictions.

An acute attack of porphyria may begin with sharp abdominal

pain. Subsequently, patients may develop agitation, hallucinations,

or seizures. Several days later, back and extremity pain followed by

weakness ensues, mimicking GBS (Pattern 1, Table 446-2). Weakness

can involve the arms or the legs and can be asymmetric, proximal, or

distal in distribution, as well as affecting the face and bulbar musculature. Dysautonomia and signs of sympathetic overactivity are common

(e.g., pupillary dilation, tachycardia, and hypertension). Constipation,

urinary retention, and incontinence can also be seen.

The CSF protein is typically normal or mildly elevated. Liver

function tests and hematologic parameters are usually normal. Some

patients are hyponatremic due to inappropriate secretion of antidiuretic hormone (Chap. 378). The urine may appear brownish in color

secondary to the high concentration of porphyrin metabolites. Accumulation of intermediary precursors of heme (i.e., d-aminolevulinic

acid, porphobilinogen, uroporphobilinogen, coproporphyrinogen, and

protoporphyrinogen) is found in urine. Specific enzyme activities can

also be measured in erythrocytes and leukocytes. The primary abnormalities on EDx are marked reductions in compound motor action

potential (CMAP) amplitudes and signs of active axonal degeneration

on needle EMG.

The porphyrias are inherited in an autosomal dominant fashion.

AIP is associated with porphobilinogen deaminase deficiency, HCP

is caused by defects in coproporphyrin oxidase, and VP is associated

with protoporphyrinogen oxidase deficiency. The pathogenesis of the

neuropathy is not completely understood. Treatment with glucose and

hematin may reduce the accumulation of heme precursors. Intravenous glucose is started at a rate of 10–20 g/h. If there is no improvement within 24 h, intravenous hematin 2–5 mg/kg per day for 3–14

days should be administered.

■ FAMILIAL AMYLOID POLYNEUROPATHY

Familial amyloid polyneuropathy (FAP) is phenotypically and genetically heterogeneous and is caused by mutations in the genes for

transthyretin (TTR), apolipoprotein A1, or gelsolin (Chap. 112). The

majority of patients with FAP have mutations in the TTR gene. Amyloid deposition may be evident in abdominal fat pad, rectal, or nerve

biopsies. The clinical features, histopathology, and EDx reveal abnormalities consistent with a generalized or multifocal, predominantly

axonal but occasionally demyelinating, polyneuropathy.

Patients with TTR-related FAP usually develop insidious onset of

numbness and painful paresthesias in the distal lower limbs in the third

to fourth decade of life, although some patients develop the disorder

later in life (Pattern 2, Table 446-2). Carpal tunnel syndrome (CTS) is

common. Autonomic involvement can be severe, leading to postural

hypotension, constipation or persistent diarrhea, erectile dysfunction,

and impaired sweating (Pattern 10, Table 446-2). Amyloid deposition

also occurs in the heart, kidneys, liver, and corneas. Patients usually

die 10–15 years after the onset of symptoms from cardiac failure or

complications from malnutrition. Because the liver produces much of

the body’s TTR, liver transplantation has been used to treat FAP related

to TTR mutations. Serum TTR levels decrease after transplantation,

and improvement in clinical and EDx features has been reported.

Both tafamidis meglumine (20 mg daily) and diflunisal (250 mg twice

daily), which prevent misfolding and deposition of mutated TTR,

appear to slow the rate of deterioration in patients with TTR-related

FAP. Recently, two different modes of gene therapy that inhibit hepatic

production of TTR have been shown to improve neurologic function

and quality of life compared to placebo in clinical trials. Inotersen,

an antisense oligonucleotide, is given subcutaneously once a week.

The main side effects are thrombocytopenia and glomerulonephritis.

Patisiran, a small interfering RNA, is give at a dose of 0.3 mg/kg

(up to 30 mg) every 3 weeks. Infusion reactions are common; therefore,

prophylactic corticosteroids, acetaminophen, and an antihistamine

should be administered.

Patients with apolipoprotein A1–related FAP (Van Allen type) usually

present in the fourth decade with numbness and painful dysesthesias in

the distal limbs. Gradually, the symptoms progress, leading to proximal

and distal weakness and atrophy. Although autonomic neuropathy is

3488 PART 13 Neurologic Disorders

not severe, some patients develop diarrhea, constipation, or gastroparesis. Most patients die from systemic complications of amyloidosis (e.g.,

renal failure) 12–15 years after the onset of the neuropathy.

Gelsolin-related amyloidosis (Finnish type) is characterized by the

combination of lattice corneal dystrophy and multiple cranial neuropathies that usually begin in the third decade of life. Over time, a

mild generalized sensorimotor polyneuropathy develops. Autonomic

dysfunction does not occur.

ACQUIRED NEUROPATHIES

■ PRIMARY OR AL AMYLOIDOSIS (SEE CHAP. 112)

Besides FAP, amyloidosis can also be acquired. In primary or AL

amyloidosis, the abnormal protein deposition is composed of immunoglobulin light chains. AL amyloidosis occurs in the setting of multiple

myeloma (MM), Waldenström’s macroglobulinemia, lymphoma, other

plasmacytomas, or lymphoproliferative disorders, or without any other

identifiable disease.

Approximately 30% of patients with AL primary amyloidosis present with a polyneuropathy, most typically painful dysesthesias and

burning sensations in the feet (Pattern 2, Table 446-2). However, the

trunk can be involved, and some patients manifest with a mononeuropathy multiplex pattern. CTS occurs in 25% of patients and may be

the initial manifestation. The neuropathy is slowly progressive, and

eventually, weakness develops along with large-fiber sensory loss. Most

patients develop autonomic involvement with postural hypertension,

syncope, bowel and bladder incontinence, constipation, impotence,

and impaired sweating (Pattern 10, Table 446-2). Patients generally die

from their systemic illness (renal failure, cardiac disease).

The monoclonal protein may be composed of IgG, IgA, IgM, or

only free light chain. Lambda (λ) is more common than κ light chain

(>2:1) in AL amyloidosis. The CSF protein is often increased (with

normal cell count), and thus, the neuropathy may be mistaken for

CIDP (Chap. 447). Nerve biopsies reveal axonal degeneration and

amyloid deposition in either a globular or diffuse pattern infiltrating

the perineurial, epineurial, and endoneurial connected tissue and in

blood vessel walls.

The median survival of patients with primary amyloidosis is <2 years,

with death usually from progressive congestive heart failure or renal

failure. Chemotherapy with melphalan, prednisone, and colchicine, to

reduce the concentration of monoclonal proteins, and autologous stem

cell transplantation may prolong survival, but whether the neuropathy

improves is controversial.

■ DIABETIC NEUROPATHY

DM is the most common cause of peripheral neuropathy in developed

countries. DM is associated with several types of polyneuropathy:

distal symmetric sensory or sensorimotor polyneuropathy, autonomic

neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies,

cranial neuropathies, and other mononeuropathies. Risk factors for the

development of neuropathy include long-standing, poorly controlled

DM and the presence of retinopathy and nephropathy.

Diabetic Distal Symmetric Sensory and Sensorimotor

Polyneuropathy (DSPN) DSPN is the most common form of

diabetic neuropathy and manifests as sensory loss beginning in the

toes that gradually progresses over time up the legs and into the fingers

and arms (Pattern 2, Table 446-2). When severe, a patient may develop

sensory loss in the trunk (chest and abdomen), initially in the midline

anteriorly and later extending laterally. Tingling, burning, deep aching

pains may also be apparent. NCS usually show reduced amplitudes

and mild to moderate slowing of conduction velocities. Nerve biopsy

reveals axonal degeneration, endothelial hyperplasia, and, occasionally,

perivascular inflammation. Tight control of glucose can reduce the

risk of developing neuropathy or improve the underlying neuropathy.

A variety of medications have been used with variable success to treat

painful symptoms associated with DSPN, including antiepileptic medications, antidepressants, sodium channel blockers, and other analgesics

(Table 446-6).

Diabetic Autonomic Neuropathy Autonomic neuropathy is

typically seen in combination with DSPN. The autonomic neuropathy

can manifest as abnormal sweating, dysfunctional thermoregulation,

dry eyes and mouth, pupillary abnormalities, cardiac arrhythmias,

postural hypotension, GI abnormalities (e.g., gastroparesis, postprandial bloating, chronic diarrhea, or constipation), and genitourinary

dysfunction (e.g., impotence, retrograde ejaculation, incontinence)

(Pattern 10, Table 446-2). Tests of autonomic function are generally

abnormal, including sympathetic skin responses and quantitative

TABLE 446-6 Treatment of Painful Sensory Neuropathies

THERAPY ROUTE DOSE SIDE EFFECTS

First-Line

Lidoderm 5% patch Apply to painful area Up to 3 patches qd Skin irritation

Tricyclic antidepressants (e.g.,

amitriptyline, nortriptyline)

PO 10–100 mg qhs Cognitive changes, sedation, dry eyes and mouth, urinary retention, constipation

Gabapentin PO 300–1200 mg tid Cognitive changes, sedation, peripheral edema

Pregabalin PO 50–100 mg tid Cognitive changes, sedation, peripheral edema

Duloxetine PO 30–60 mg qd Cognitive changes, sedation, dry eyes, diaphoresis, nausea, diarrhea, constipation

Second-Line

Carbamazepine PO 200–400 mg q 6–8 h Cognitive changes, dizziness, leukopenia, liver dysfunction

Phenytoin PO 200–400 mg qhs Cognitive changes, dizziness, liver dysfunction

Venlafaxine PO 37.5–150 mg/d Asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry

mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as

abnormal ejaculation/orgasm and impotence

Tramadol PO 50 mg qid Cognitive changes, gastrointestinal upset

Third-Line

Mexiletine PO 200–300 mg tid Arrhythmias

Other Agents

EMLA cream Apply cutaneously qid Local erythema

2.5% lidocaine

2.5% prilocaine

Capsaicin 0.025–0.075% cream Apply cutaneously qid Painful burning skin

Source: Modified from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill, 2016, Table 22-3, p. 485.