LIFELONG LEARNING IN NEUROLOGY ®

ALS and Other Motor Neuron Diseases

Tiryaki, Ezgi MD; Horak, Holli A. MD, FAAN. Continuum (Minneap Minn). October 2014;
20(5 Peripheral Nervous System Disorders): 1185Y1207.

Abstract
Purpose of Review:
This review describes the most common motor neuron disease, ALS. It discusses the diagnosis
and evaluation of ALS and the current understanding of its pathophysiology, including new
genetic underpinnings of the disease. This article also covers other motor neuron diseases, reviews
how to distinguish them from ALS, and discusses their pathophysiology.
Recent Findings:
In this article, the spectrum of cognitive involvement in ALS, new concepts about protein
synthesis pathology in the etiology of ALS, and new genetic associations will be covered.
This concept has changed over the past 3 to 4 years with the discovery of new genes and genetic
processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of
sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43),
for instance, has been shown to cause frontotemporal dementia as well as some cases of
familial ALS, and is associated with frontotemporal dysfunction in ALS.
Summary:
The anterior horn cells control all voluntary movement: motor activity, respiratory, speech, and
swallowing functions are dependent upon signals from the anterior horn cells. Diseases that damage the
anterior horn cells, therefore, have a profound impact. Symptoms of anterior horn cell loss (weakness,
falling, choking) lead patients to seek medical attention. Neurologists are the most likely practitioners
to recognize and diagnose damage or loss of anterior horn cells. ALS, the prototypical motor neuron
disease, demonstrates the impact of this class of disorders. Most patients (without tracheostomy) die within
2 to 3 years of diagnosis from paralysis and respiratory failure. ALS and other motor neuron diseases
can represent diagnostic challenges. Neurologists are often called upon to serve as a ‘‘medical
home’’ for these patients: coordinating care, arranging for durable medical equipment, and leading
discussions about end-of-life care with patients and caregivers. It is important for neurologists to be
able to identify motor neuron diseases and to evaluate and treat patients affected by them.

Key Points
& A motor unit is one motor neuron, its axon, and all the individual muscle fibers it
innervates.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & EMG performed for suspected ALS must include at least three regions of the neuraxis
to confirm a widespread pattern beyond regional damage from radiculopathies.
& It is not uncommon for fasciculations to go unrecognized by the patient and only be
noticed by a family member or physician.
& Progression and spread of symptoms are hallmarks of ALS.
& ALS is often described as painless, but muscle cramps can be quite uncomfortable and,
at times, painful.
& Many neurodegenerative conditions are associated with pseudobulbar, which is not
unique to ALS.
& The distinction of familial and sporadic ALS based on family history may become
obsolete over time as new genes are discovered.
& Neuronal cytoplasmic protein aggregation and defective RNA metabolism appear to
be common pathogenic mechanisms involved in ALS and possibly in other
neurodegenerative disorders.
& Focal onset of weakness with muscle wasting and brisk reflexes that progresses and
spreads over time prompts the consideration of ALS as the underlying cause.
& The diagnosis of ALS is suspected by the presence of upper motor neuron and
lower motor neuron degeneration within the same region.
& Preserved reflexes may indicate hyperreflexia in wasted muscles.
& According to El Escorial criteria, upper motor neuron and lower motor neuron
involvement in three regions constitutes definite ALS.
& Any patient with bulbar involvement, by definition, has symptoms above the cervical
level and is, therefore, not likely to have a cervical myelopathy.
& The El Escorial criteria help in ruling out mimics of ALS. If there are atypical features or
lack of symptom progression that spreads into other anatomic regions, then reassessment
of the diagnosis is recommended.
& Cognitive impairment may decrease acceptance of care interventions and impair
decision-making.
& All ALS patients should be encouraged to participate in the National ALS Registry
wwwn.cdc.gov/als/.
& Weakness in multifocal motor neuropathy is out of proportion to the degree of atrophy.
& Spinal bulbar muscular atrophy patients have prominent tongue and perioral fasciculations.
& There are no specific tests for monomelic amyotrophy; therefore, initially, this disease
may be difficult to distinguish from focal ALS. Over time monomelic amyotrophy
will not progress and no upper motor neuron features manifest.

Charcot-Marie-Tooth Disease and

Other Inherited Neuropathies
Saporta, Mario A. MD, PhD. Continuum (Minneap Minn). October 2014; 20(5 Peripheral Nervous
System Disorders): 1208Y1225.

Abstract
Purpose of Review:
Inherited peripheral neuropathies are among the most common genetic neuromuscular disorders
worldwide. However, their diagnosis can be challenging due to genotypic and phenotypic

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

variability. Charcot-Marie-Tooth disease (CMT), the most common form, is associated with
mutations or copy-number variations in over 70 genes, representing proteins with fundamental
roles in the development and function of Schwann cells and peripheral axons. Other genetic
peripheral neuropathies are associated with multisystem manifestations, including familial
amyloid neuropathy and neuropathies associated with metabolic or other genetic syndromes. This
article reviews the most recent discoveries in the field and how they are changing the way
neurologists diagnose this specific group of peripheral neuropathies.
Recent Findings:
In the past few years, several large cohort studies on the molecular diagnosis of CMT have been
published, providing guidelines for genetic testing in clinical practice. In the same period,
next-generation sequencing technology has accelerated the discovery of new CMT genes,
expanding our knowledge on genotype-phenotype correlations.
Summary:
Recent advances in sequencing technology and genotype-phenotype correlation studies are
changing the way neurologists diagnose inherited neuropathies. New therapeutic strategies for
familial amyloid neuropathy are paving the way for innovative treatments for genetic neuropathies.

Key Points
& Currently, over 70 distinct genes have been associated with at least one of the
Charcot-Marie-Tooth disease phenotypes, which include motor and sensory
neuropathies, predominantly autonomic and sensory neuropathies, and pure motor
neuropathies.
& In Western countries with mixed ethnicities, autosomal dominant and X-linked
dominant forms of Charcot-Marie-Tooth disease predominate. However, in countries
with homogenous or isolated population or where consanguineous marriages are part of
the social norm, autosomal recessive forms can be seen more frequently and may even
be the most common type of Charcot-Marie-Tooth disease diagnosed.
& More than 90% of Charcot-Marie-Tooth disease cases in which a molecular diagnosis has
been reached are associated with changes in four genes: PMP22, GJB1, MFN2, and MPZ.
& Any length-dependent neuropathy can potentially have a genetic etiology, and it is
very important to keep this in mind while making the differential diagnosis of patients
with peripheral neuropathies.
& Features that can be helpful in raising the suspicion of a genetic neuropathy include
symptom onset during infancy, long and slowly progressing symptoms, foot deformities
and lack of positive sensory symptoms despite clear sensory involvement.
& Identifying characteristic phenotypes or associated symptoms can help guide genetic testing.
& The classic Charcot-Marie-Tooth disease phenotype includes normal initial development
followed by gradual distal weakness and sensory loss appearing within the first 2 decades
of life, reduced deep tendon reflexes, and skeletal deformities in the feet.
& The classic Charcot-Marie-Tooth disease phenotype is strongly associated with
Charcot-Marie-Tooth disease type 1A representing 55% to 60% of all
Charcot-Marie-Tooth disease cases with a positive molecular test.
& In cases presenting with a classic Charcot-Marie-Tooth disease phenotype, but which are
negative for the PMP22 duplication, special attention should be given to the family
history. If no male-to-male transmission can be identified in the family, X-linked
Charcot-Marie-Tooth is the most probable diagnosis.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Patients with a classic Charcot-Marie-Tooth disease type 1 phenotype and male-to-male
transmission in the family who test negative for the PMP22 duplication should then
be tested for Charcot-Marie-Tooth disease type 1B, which is the third most common
cause of Charcot-Marie-Tooth disease type 1.
& Dejerine-Sottas disease is currently used primarily to denote severe early-onset clinical
phenotypes regardless of the inheritance pattern. These cases are usually associated
with PMP22 duplication or point mutations, MPZ mutations, and, in rare cases, other
Charcot-Marie-Tooth disease type 1 genes or recessive forms.
& Charcot-Marie-Tooth disease type 2 (CMT2) accounts for approximately 25% to
30% of all Charcot-Marie-Tooth disease cases. However, this prevalence may be an
underestimation, as only a minority of CMT2 patients have a molecular diagnosis
(approximately 25%).
& Most other axonal Charcot-Marie-Tooth disease types are of rare occurrence and
difficult to diagnose. Relying on associated symptoms to narrow the list of genes to
be tested is a common strategy in specialized centers.
& The nomenclature ‘‘intermediate Charcot-Marie-Tooth disease’’ should be used to
define families with individuals presenting with median motor nerve conduction velocities
in the demyelinating range while other affected members demonstrate velocities in the
axonal range.
& Mutations in GJB1, MPZ, DNM2, YARS, IFN2, and GNB4 have all been associated
with intermediate Charcot-Marie-Tooth disease and therefore should be tested in
such cases.
& Recessive forms of Charcot-Marie-Tooth disease are suspected in families with multiple
affected siblings and asymptomatic parents or in patients with no family history but
specific phenotypes.
& Distal hereditary motor neuropathies are a distinct phenotype of inherited neuropathies,
characterized by a length-dependent, slowly progressive, exclusively motor neuropathy.
& Hereditary sensory and autonomic neuropathies designate phenotypes in which sensory or
autonomic symptoms predominate, although a minor motor component can still be observed.
& The most prevalent types of hereditary sensory and autonomic neuropathies are
autosomal recessive, with congenital or early onset presentations. However, autosomal
dominant forms are also seen, with later onset of symptoms.
& As the technology develops and prices drop, next-generation sequencing will probably
become the standard method for molecular diagnosis of patients with
Charcot-Marie-Tooth disease, as it will soon be less expensive than sequencing multiple
single genes using direct sequencing techniques.
& Patients with inherited neuropathies are best managed by a multidisciplinary team of
professionals, including genetic counselors, physical and occupational therapists, nurses,
neurologists, orthopedic surgeons, and physiatrists.
& The decision to have genetic testing or not should always rest with the patient. Reasons
for pursuing a molecular diagnosis include family planning, etiologic elucidation of
the neuropathy, eligibility to enroll in type-specific clinical trials, and application for
some government benefits. Issues associated with testing, on the other hand, include
psychological distress, social and work discrimination, and high financial cost of the test.
& Patients with inherited neuropathies should be periodically screened for diseases that
may exacerbate their impairment, including diabetes mellitus, hypothyroidism, vitamin
deficiencies, and monoclonal gammopathies, and correction of any abnormality should be
done promptly.
& Assistive devices, including inserts and ankle-foot orthoses, and occupational therapy
focused on developing tools and strategies to cope with activities of daily living,

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 should be used to improve functionality and quality of life of patients with
Charcot-Marie-Tooth disease.
& Transthyretin familial amyloid polyneuropathy usually presents as a small fiber
neuropathy around the third or fourth decade of life, which progresses to a large fiber
sensorimotor severe neuropathy. Autonomic dysfunction is common, affecting the
cardiovascular, gastrointestinal, and genitourinary systems. The disease progresses
relentlessly, with patients usually dying within 10 years of diagnosis.
& Metabolic disorders are another cause of multisystem diseases that also affect the peripheral
nervous system. This group includes some leukodystrophies (metachromatic, Krabbe,
adrenoleukodystrophy), peroxisomal diseases (Fabry, Refsum), lipoprotein deficiencies
(Tangier, cerebrotendinous xanthomatosis), porphyrias, and mitochondrial diseases.

Diabetic Neuropathies
Russell, James W. MD, MS, FRCP, FACP, FAAN; Zilliox, Lindsay A. MD. Continuum
(Minneap Minn). October 2014; 20(5 Peripheral Nervous System Disorders): 1226Y1240.

Abstract
Purpose of Review:
This article provides an overview for understanding the diagnosis, pathogenesis, and management
of diabetic neuropathy.
Recent Findings:
New information about the pathogenesis of diabetic neuropathy continues to emerge, which
will lead to identifying new drug targets. It is clear that the natural history of diabetic neuropathy
is changing and the rate of progression is slowing. This is likely because of a combination of
earlier diagnosis, improved glycemic management, and improved control of related complications
such as hyperlipidemia and hypertension. Early diagnosis is critical, and small fiber neuropathy
or subclinical diabetic neuropathy may be reversed or significantly improved with appropriate
intervention. The American Academy of Neurology recently published guidelines for the treatment
of painful diabetic neuropathy.
Summary:
Diabetic neuropathy is common and can present with varied clinical presentations discussed
in this article. Although treatment currently focuses on pain management, attention should be
paid to potential risk factors for neuropathy. For example, glycemic control, hyperlipidemia,
and hypertension should be managed with diet, exercise, and medications. Class I or II clinical
studies indicate that pregabalin, duloxetine, amitriptyline, gabapentin, and opioids are effective
in the management of diabetic neuropathic pain.

Key Points
& Neuropathy is not only a late complication of diabetes mellitus, but also can develop
at any time during the course of the disease. It is increasingly recognized in patients
with prediabetes who are at high risk of developing diabetes mellitus.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Two-hour glucose tolerance testing should be ordered in patients with an otherwise
idiopathic neuropathy to examine for the presence of prediabetes.
& The most common complication in diabetes mellitus is peripheral neuropathy.
& Sympathetic vasomotor changes often seen with small fiber neuropathies include
pallor alternating with rubor, cyanosis, and mottling.
& Small fiber neuropathies may not have any abnormalities on nerve conduction studies
and can be further evaluated with skin biopsy and measurement of the intraepidermal
nerve fiber density or sudomotor testing.
& The presence of cardiac autonomic neuropathy is associated with a two to five times
increased risk of all-cause mortality.
& Symptoms of resting tachycardia, palpitations, exercise intolerance, or orthostatic
hypotension may indicate cardiac autonomic neuropathy.
& Diabetic lumbosacral radiculoplexus neuropathy should be suspected in a patient with
diabetes mellitus who reports acute, unilateral pain in the hip or thigh.
& Treatment-induced neuropathy of diabetes mellitus is an acute painful neuropathy.
It is a reversible disorder that is seen in patients with previously uncontrolled diabetes
mellitus who rapidly improve their glycemic control.
& Diabetic neuropathic cachexia is a partially reversible disorder that presents with
unintentional weight loss and an acute painful neuropathy in patients with poorly
controlled diabetes mellitus. Depression is very common.
& The presence of proximal or truncal dysesthesia may be a clue to the diagnosis of
diabetic neuropathic cachexia.
& Severe diabetic neuropathy can mimic chronic inflammatory demyelinating
polyradiculoneuropathy on nerve conduction studies, and the diagnostic distinction is
important for determining treatment options.
& If possible, patients with hypertension and a diabetic neuropathy should be taken off
thiazide diuretics and placed on an angiotensin-converting enzyme inhibitor or an
angiotensin-receptor blocker if needed.
& Strict glucose control can delay the onset or slow the progression of diabetic neuropathy,
but there is an increased risk of hypoglycemic events.
& Patients with prediabetes or early diabetes mellitus and neuropathy should be offered
dietary and exercise counseling.
& First-line agents for the treatment of painful diabetic neuropathy include amitriptyline,
venlafaxine, duloxetine, gabapentin, and pregabalin.

Acquired Immune Demyelinating

Neuropathies
Dimachkie, Mazen M. MD, FAAN, FANA; Saperstein, David S. MD. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1241Y1260.

Abstract
Purpose of Review:
Acquired immune demyelinating neuropathies refer to a group of disorders that share overlapping
sensory, motor, and autonomic clinical, laboratory, and electrodiagnostic features. It is important

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

to recognize acquired immune demyelinating neuropathies as they are generally responsive to
immunosuppressive or immunomodulatory therapies.

Recent Findings:
This article reviews recently developed early prognostic tools in Guillain-Barré syndrome and
discusses the evolving understanding of chronic demyelinating phenotypes with differing
treatment responsiveness.

Summary:
While weakness and numbness progress over 2 to 4 weeks in Guillain-Barré syndrome, they
continue to evolve beyond 8 weeks in chronic inflammatory demyelinating
polyradiculoneuropathy and over 4 to 8 weeks in subacute inflammatory demyelinating
polyradiculoneuropathy. Acquired immune demyelinating neuropathies present uncommonly as
variants with predominance of ocular, bulbar, sensory, autonomic, or motor manifestations in
addition to regional variants, such as paraparetic acquired immune demyelinating neuropathies.
Establishing the correct diagnosis is important as these immune disorders differ in response
to corticosteroids and other immunosuppressive therapies.

Key Points
& The Landry-Guillain-Barré-Strohl syndrome, commonly referred to as Guillain-Barré
syndrome (GBS), is an acute monophasic immune-mediated polyradiculoneuropathy
with an incidence ranging from 1.1 to 1.8 per 100,000.
& Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) begins most
commonly with acroparesthesia, followed 7 to 10 days later by symmetric ascending
weakness, which is associated with severe radicular lumbar and neuropathic pain in
up to two-thirds of cases.
& Dysautonomia, most commonly manifesting as sinus tachycardia, is observed in
two-thirds of cases of AIDP.
& In the United States, AIDP accounts for 80% of Guillain-Barré syndrome cases.
& Fisher syndrome represents roughly 5% of Guillain-Barré syndrome cases and consists
of a triad of ophthalmoparesis, areflexia, and gait ataxia, but patients often have partial
presentations. Another less common variant where weakness is not predominant is
Bickerstaff brainstem encephalitis, which is associated with ophthalmoparesis,
hyperreflexia, gait ataxia, and encephalopathy.
& A prodromal illness occurs in the 4 weeks preceding Guillain-Barré syndrome in
60% to 70% of cases.
& Surveillance data of the 2009 to 2010 H1N1 (swine flu) immunization indicated a
modest and acceptable increase in Guillain-Barré syndrome risk of 0.8 cases per
1 million vaccinations.
& When Guillain-Barré syndrome occurs within 6 weeks of receiving the flu vaccine,
the question of future immunization is difficult to answer. A risk-benefit analysis on a
case-by-case basis should guide whether future immunization 6 to 12 months later is
recommended in such Guillain-Barré syndrome patients.
& AIDP is the result of a T-cellYdriven autoimmune response targeting peripheral
nerve myelin.
& The T-cellYdriven autoimmune response in AIDP results in myelin stripping and,
in severe cases, bystander axon loss.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Diagnostic criteria for Guillain-Barré syndrome were proposed 2 decades ago and
require laboratory support and exclusion of mimics.
& It is critically important to obtain an initial forced vital capacity and negative inspiratory
force on presentation of patients with Guillain-Barré syndrome as these predict incipient
respiratory failure well before hypoxemia supervenes on pulse oximetry or arterial
blood gas testing.
& CSF evaluation in Guillain-Barré syndrome shows a nonspecifically elevated protein
in 90% of cases in the absence of white blood cell elevation (less than 20/mm3), the
so-called albuminocytologic dissociation. CSF protein elevation may be delayed; in
those with normal initial studies, a repeat lumbar puncture in 5 to 7 days may be
supportive of the diagnosis.
& Depending on the criteria, the sensitivity of nerve conduction study may be as
low as 22% in early AIDP and rise to 87% at 5 weeks. Therefore, it is important
not to delay treatment in patients who do not have supportive nerve conduction
study findings.
& A sural sparing pattern is observed in one-third of cases of Guillain-Barré syndrome,
with normal sural sensory nerve action potential amplitude and reduced or absent
median or ulnar sensory nerve action potential amplitude.
& Distal compound muscle action potential duration prolongation beyond 8.5 ms was
found in 5/13 (38%) of patients with AIDP with negative electrodiagnostic studies,
and in only 9%of ALS cases.
& If routine testing is not diagnostic in Guillain-Barré syndrome, it is important to test
contralateral limb distal motor nerves, proximal nerves, and cranial nerves, or even to
repeat nerve conduction studies in 3 to 5 days.
& It is fundamental to provide excellent general supportive care in Guillain-Barré syndrome.
& Overall, the guiding principle is not to overtreat dysautonomia in Guillain-Barré
syndrome since blood pressure will often fluctuate.
& Plasma exchange within 2 to 4 weeks of onset was the first treatment shown to be
effective in Guillain-Barré syndrome based on randomized controlled trials. It reduces
the time to walk unaided by 32 to 41 days and time on ventilator by 2 weeks.
& IVIg was the second treatment shown to be effective in Guillain-Barré syndrome.
Both treatments (IVIg and plasma exchange) are equally effective at 4 weeks.
& Plasma exchange followed by IVIg is not more effective than either therapy alone.
& Oral corticosteroids are contraindicated in Guillain-Barré syndrome for concern of
worse outcome. Adding IV methylprednisolone to IVIg is no better than placebo.
& The mean time to onset of recovery of Guillain-Barré syndrome is 28 days and to
complete recovery is 200 days. Most patients (80%) resume the ability to walk
independently by 6 months, with some experiencing persistent long-term sensory
or autonomic symptoms of varying severity.
& Useful predictive tools derived from prior Guillain-Barré syndrome studies include
the Erasmus Guillain-Barré syndrome outcome score at 2 weeks and the modified
Erasmus Guillain-Barré syndrome Outcome Score at week 1.
& Patients and their families can be advised about the long-term prognosis as early as
1 or 2 weeks as well as risk of respiratory failure in the first week of admission by
2using the online IGOS GBS Prognosis Tool.
& A temporal variant group consists of patients who progress for longer than 4 weeks
but less than 8 weeks, and therefore do not fall neatly into either AIDP or chronic
inflammatory demyelinating polyneuropathy groups.
& In one study, subacute inflammatory demyelinating polyneuropathy (SIDP) patients
were treated with prednisone and some received an IVIg course as well; all improved

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 and were able to taper off and stop prednisone. Definite SIDP had all of the CIDP
characteristics with three exceptions: a higher rate of antecedent infection, no relapses,
and a high rate (69%) of full recovery.
& The chronic acquired demyelinating polyneuropathies are immune-mediated
neuropathies with a number of common features.
& Although patients with chronic acquired demyelinating polyneuropathies may have
exclusively distal weakness, when only distal clinical features are present, the differential
diagnosis is much broader and includes toxic, metabolic, hereditary, and vasculitic disorders.
& When symmetric proximal and distal involvement is not present, the likelihood of
identifying a treatable demyelinating disorder is lower.
& CIDP is caused by immune-mediated demyelination. The precise pathophysiology
has not been elucidated, but T-cell activation is the predominant factor. Important
roles are also played by macrophages and humoral factors.
& The three most important laboratory studies that support the diagnosis of CIDP are
CSF examination, nerve conduction studies, and nerve biopsy.
& CSF testing is not necessary in every patient suspected of CIDP; however, all patients
with suspected CIDP should be checked for a serum paraprotein.
& In most patients with CIDP, a nerve biopsy is not necessary.
& While nerve conduction study is an important and useful tool, the overall clinical
presentation is most helpful in a making a diagnosis.
& Sensory nerve conduction studies currently have no accepted role in establishing a
diagnosis of a demyelinating polyneuropathy.
& The studies comparing criteria are all limited by retrospective evaluation and lack of
a gold standard.
& The purpose of nerve conduction study criteria is to minimize the number of patients
without demyelinating neuropathies from being falsely diagnosed with CIDP while
not excluding too many patients who do have CIDP.
& Randomized, controlled trials have demonstrated the efficacy of corticosteroids,
plasma exchange, and IVIg for the treatment of CIDP. The efficacy of these therapies
appears to be similar. Each is an acceptable first-line therapy, although the need for
facilities capable of providing outpatient plasma exchange and prolonged IV access
usually relegates plasma exchange to a second- or third-line agent.
& The ideal IVIg treatment regimen has not been determined. The most common strategy
is to give a loading dose of 2 g/kg. This is usually administered over 2 to 5 days,
with most patients able to receive this dose over 2 days.
& Some form of repeat IVIg dosing is necessary, because, in most cases, it can take an
average of 3 months for maximal improvement to occur.
& Approximately two-thirds of CIDP patients will improve with IVIg.
& Although patients with CIDP can be maintained on long-term IVIg treatment, most
experts advocate trying to decrease or discontinue IVIg.
& Clinical trial data show that approximately 50% of patients with CIDP will remain
stable at least 6 months after IVIg is stopped, but the other 50% will deteriorate and
require a resumption of treatment.
& Plasma exchange is often used for patients with CIDP who are very weak or experience
a relapse while on another therapy. However, plasma exchange can be used as a
long-term therapy.
& While retrospective series suggest about one-third of patients with CIDP will
respond to other immunomodulating medications, high-level evidence for these
therapies does not exist, and many are skeptical of their efficacy. Therefore, the
preference of the authors of this article is to use IVIg, corticosteroids, and plasma

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 exchange, alone or in combination, before considering another form of therapy for
patients with CIDP.
& The majority of patients with a distal acquired demyelinating symmetric neuropathy
phenotype will have a monoclonal protein. It is important to distinguish patients with
distal acquired demyelinating symmetric neuropathy from those with CIDP because
their clinical course and response to therapy are very different.
& It is important to distinguish multifocal motor neuropathy from motor neuron disease,
as the former is a treatable disorder.
& Anti-GM1 antibodies are not necessary for the diagnosis of multifocal motor neuropathy.
& Conduction block is not essential for the diagnosis of multifocal motor neuropathy
if other features of demyelination are present.
& It is unclear how to treat patients with multifocal motor neuropathy who do not respond
to IVIg (or subcutaneous immunoglobulin).
& Multifocal acquired demyelinating sensory and motor neuropathy is not associated with
anti-GM1 antibodies.
& Patients with multifocal acquired demyelinating sensory and motor neuropathy may
respond to corticosteroids (similar to CIDP), as opposed to MMN patients in whom
corticosteroids are usually avoided.

Acquired Immune Axonal Neuropathies

Bril, Vera BSc, MD, FRCPC; Katzberg, Hans D. MD, MSC, FRCPC. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1261Y1273.

Abstract
Purpose of Review:
This article discusses the clinical features, pathophysiology, and management of primary and
secondary acquired immune axonal neuropathies.
Recent Findings:
Acute motor axonal neuropathy (AMAN) and acute motorsensory axonal neuropathy (AMSAN)
are well-characterized variants of Guillain-Barré syndrome. Although there are many collagen
vascular disorders associated with vasculitic neuropathy, a quarter of cases have been described
to be due to nonsystemic vasculitis of the peripheral nervous system. Enhanced surveillance
and aggressive treatment of conditions such as cryoglobulin-related vasculitic neuropathy with
cyclophosphamide, rituximab, and alfa interferons has led to improved morbidity and mortality,
however, many cases of immune axonal acquired neuropathy are still associated with
poor outcomes.
Summary:
Characterizing the clinical and electrophysiologic phenotype can help diagnose conditions
such as AMAN, AMSAN, nonsystemic vasculitic neuropathy, and immune small fiber
neuropathy, while careful evaluation of systemic features is key to identifying secondary
immune axonal neuropathies such as vasculitic neuropathy related to collagen vascular

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

disease. Additional research is needed to determine the exact immune pathogenesis and
optimized treatment regimens for all acquired immune axonal neuropathies.

Key Points
& The presence of a painful mononeuropathy multiplex and systemic involvement such
as weight loss, rash, or constitutional symptoms should prompt investigation for
vasculitic neuropathy.
& In contrast to chronic inflammatory demyelinating polyradiculoneuropathy and
multifocal motor neuropathy, many acquired axonal immune neuropathies, particularly
systemic and nonsystemic vasculitic neuropathy, are unresponsive to IV immunoglobulin
and require a higher level immunosuppression.
& A painful mononeuropathy not across a site of compression should prompt a
comprehensive evaluation for systemic vasculitis.
& Polyarteritis nodosa is a systemic neuropathy with one of the highest prevalences of
neuropathy (65% to 75%), particularly neuropathy as a presenting feature of the disease (30%).
& One major distinguishing feature between polyarteritis nodosa and microscopic
polyangiitis is that the latter has positive antibodies to myeloperoxidaseYantineutrophil
cytoplasmic antibodies which are absent in cases of polyarteritis nodosa.
& Collagen vascular diseases such as rheumatoid arthritis and systemic lupus erythematosus
have high prevalence of neuropathy; however, these more commonly present with a
sensorimotor polyneuropathy rather than a mononeuropathy multiplex pattern.
& Cryoglobulinemia is associated with infections such as hepatitis C in over 90% of cases;
polyclonal mixed IgG (type III) cryoglobulinemia is most commonly associated with
neuropathy.
& Management of cryoglobulinemia should be aimed not only at reducing the level of
cryoglobulin and organ dysfunction, but monitoring for complications associated with
hepatitis such as hepatocellular carcinoma, which can occur in 10% of cases.
& Facial palsy, uveitis, fever, and parotid enlargement associated with sarcoidosis is termed
Heerfordt syndrome.
& Infections such as hepatitis B and C, cytomegalovirus, human T-cell lymphotropic
virus-1, Lyme disease, and leprosy can be associated with immune axonal neuropathy;
however, these infections rarely cause classic vasculitic changes and as such are most
accurately called infectious vasculopathy rather than vasculitis.
& Most cases of immune axonal neuropathy can be diagnosed using a comprehensive
clinical assessment and testing which includes urinalysis, serology, imaging, CSF
analysis, and electrophysiology. On occasion, nerve biopsy is indicated when the
above tests are not helpful, particularly when peripheral nerve vasculitis is suspected.
& Perineuritis is a rare acquired immune axonal neuropathy that can present similarly to
peripheral nerve vasculitis, but is characterized by inflammation of the perineurium as
opposed to the vasa nervorum.
& Campylobacter jejuni is the most common infection preceding acute motor axonal
neuropathy but is also associated with development of acute inflammatory demyelinating
polyradiculoneuropathy.
& Immune pathology in acute motor axonal neuropathy is directed at nodal and paranodal
axolemma in contrast to segmental demyelination seen in acute inflammatory
demyelinating polyradiculoneuropathy.
& Absence of facial weakness may help distinguish acute motor axonal neuropathy from
acute inflammatory demyelinating polyradiculoneuropathy.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Immune small fiber neuropathy can occur in the setting of systemic collagen vascular
conditions (particularly Sjögren syndrome), as an idiopathic primary small fiber immune
neuropathy, or in primary neuromuscular conditions such as chronic inflammatory
demyelinating polyradiculoneuropathy, acute motor-sensory axonal neuropathy, or
Guillain-Barré syndrome.

Infectious Neuropathies
Hehir II, Michael K. MD; Logigian, Eric L. MD, FAAN. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1274Y1292.

Abstract
Purpose of Review:
Infections are important, potentially treatable causes of peripheral nervous system disease.
This article reviews the clinical presentation and management of several common peripheral
nervous system diseases due to viral, bacterial, spirochetal, and parasitic infections.
Recent Findings:
The clinical presentation and evaluation of infectious peripheral nervous system diseases are
well established. Advances in the treatment and, in some cases, the prevention of these
diseases are still evolving.
Summary:
A diverse range of peripheral nervous system diseases, including peripheral neuropathy,
radiculopathy, radiculomyelopathy, cranial neuropathy, and motor neuropathy, are caused
by bacterial, viral, and parasitic infections. In some patients, peripheral neuropathy may be a
side effect of anti-infectious drugs. This article discusses the clinical presentation, evaluation,
and treatment of patients with infectious peripheral nervous system diseases.
Numerous infectious agents can cause peripheral nervous system disease; infectious neuropathies
are important to recognize as they are potentially treatable. This article discusses several common
peripheral nervous system diseases caused by viral, bacterial, spirochetal, and parasitic infections,
as well as some peripheral nerve disorders caused by adverse effects of the treatments of these
infectious diseases.

Key Points
& One in three people will develop herpes zoster in their lifetime. Acute herpes zoster
and postherpetic neuralgia negatively impact quality of life, reduce work productivity,
and result in a large overall health care expense.
& Herpes zoster ophthalmicus may threaten vision; patients should be referred urgently to
an ophthalmologist.
& Herpes zoster may occasionally cause segmental paresis of cranial, limb, or trunk muscles.
& Immunocompromised patients have a 20 to 100 times greater risk of herpes zoster
than age-matched controls.
& Patients with disseminated herpes zoster and patients who are immunocompromised
should be treated more aggressively with IV acyclovir.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Varicella vaccination in patients older than age 50 represents an important strategy to
prevent herpes zoster and postherpetic neuralgia.
& The varicella-zoster virus vaccine is a live vaccine and cannot be administered to
immunocompromised patients.
& The varicella-zoster virus vaccine can be considered prior to starting immunosuppression
in selected neurologic patients who can safely delay immunosuppressant medications.
& Similar to varicella-zoster virus, immunocompromised patients and patients with rapidly
progressive herpes simplex virus type 2 should receive IV antiviral agents.
& A painful sensory neuropathy is a common complication of HIV.
& Incidence of HIV neuropathy remains high even as treatment for HIV advances.
Development of neuropathy does not correlate with viral load or CD4 counts.
& Neuropathic pain is a prominent component of hepatitis C virus neuropathy.
& Most cases of hepatitis C virusYassociated neuropathy are associated with the
presence of mixed cryoglobulinemia; rare cases occur in the absence of serum
cryoglobulinemia.
& Treatment with antiviral agents and some immunosuppressants may improve neuropathy
in patients with hepatitis C.
& Leprosy is rare in North America, but should be considered in any patient from a
developing country with skin lesions, cutaneous sensory loss, thickened nerves to
palpation, or focal mononeuropathies.
& The clinical manifestations of leprosy depend on the host immune response and fall
within a spectrum from tuberculoid disease (in which the skin lesions are few, the sensory
loss more confined to the cutaneous lesion, and the organisms difficult to demonstrate)
to lepromatous disease (in which the skin lesions are numerous, the sensory loss more
generalized, and the organisms are prominent on smear or biopsy).
& In contrast to length-dependent polyneuropathies, leprosy presents with relative sparing
of tendon jerks, position and vibratory sense, and noncutaneous autonomic function.
& Mycobacterium leprae is responsive to antibiotics. Once the diagnosis is confirmed,
treatment should be initiated promptly with a multidrug regimen to prevent progressive
neuropathy, late sequelae, and spread of the disease to others.
& Lyme disease is caused by a tick-borne spirochete, Borrelia burgdorferi. In North
America, the disease is endemic in the Northeast, northern Midwest, and West.
& Lyme disease begins when the tick transmits the organism to the skin, resulting in a
characteristic skin rash (erythema migrans). If untreated, early localized disease in
the skin may become hematogenously disseminated to the nervous system.
& Early neurologic Lyme disease is distinctive with one or more components of the
characteristic triad: meningitis, cranial neuritis, and radiculoneuritis. A smaller number
of patients may develop a milder, sensorimotor polyradiculoneuropathy typically
occurring later in the course of the illness.
& All neuroborreliosis syndromes are responsive to 2 to 4weeks of antibiotics. Residual
symptoms do not respond to continued courses of antibiotics.

Peripheral Neuropathy Due to Vitamin

Deficiency, Toxins, and Medications
Staff, Nathan P. MD, PhD; Windebank, Anthony J. MD, FAAN. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1293Y1306.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Abstract
Purpose of Review:
Peripheral neuropathies secondary to vitamin deficiencies, medications, or toxins are frequently
considered but can be difficult to definitively diagnose. Accurate diagnosis is important since
these conditions are often treatable and preventable. This article reviews the key features of different
types of neuropathies caused by these etiologies and provides a comprehensive list
of specific agents that must be kept in mind.

Recent Findings:
While most agents that cause peripheral neuropathy have been known for years, newly developed
medications that cause peripheral neuropathy are discussed.

Summary:
Peripheral nerves are susceptible to damage by a wide array of toxins, medications, and
vitamin deficiencies. It is important to consider these etiologies when approaching patients with
a variety of neuropathic presentations; additionally, etiologic clues may be provided by other
systemic symptoms. While length-dependent sensorimotor axonal peripheral neuropathy is the
most common presentation, several examples present in a subacute severe fashion, mimicking
Guillain-Barré syndrome.

Key Points
& Acquiring a detailed history is crucial to diagnosis of neuropathies caused by toxic agents
and vitamin deficiencies.
& In a neuropathy with significant asymmetry, polyradicular, or mononeuritis multiplex
presentation, other etiologies should be explored further, even in the setting of
documented toxicity or vitamin deficiency.
& Causes for vitamin B12 deficiency include pernicious anemia, strict veganism, gastric
bypass, prolonged antacid use, atrophic gastritis, or diseases of the terminal ileum
(eg, resection, Crohn disease).
& Copper deficiency may look very clinically similar to vitamin B12 deficiency and should
be investigated in parallel with patients with a myeloneuropathy presentation.
& Vitamin B6 is unusual in that it is associated with peripheral neuropathy either when
deficient or in excess.
& Neuropathy due to thiamine deficiency has many presentations, including
length-dependent sensorimotor, cranial nerve, and motor-predominant polyneuropathy,
all of which may precede cognitive and systemic symptoms.
& It has been difficult to determine whether alcohol directly causes neuropathy or if
its association with neuropathy is due more to chronic malnutrition and vitamin
deficiencies in alcoholics.
& Intoxication from arsenic or thallium is preceded by severe gastrointestinal illness,
and the neuropathy may mimic Guillain-Barré syndrome.
& Toxic exposure from industrial agents may be more likely to occur in people using
these agents for personal use or in small businesses.
& Newer chemotherapy agents approved over the past several years continue to have
frequent side effects of peripheral neuropathy.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Ingestion of toxic seafood may be associated with peripheral nerve disorders, which often
presents as a syndrome of gastroenteritis and perioral paresthesia.

Paraproteinemic Neuropathies
Mauermann, Michelle L. MD. Continuum (Minneap Minn). October 2014;
20(5 Peripheral Nervous System Disorders): 1307Y1322.

Abstract
Purpose of Review:
Monoclonal gammopathies are common in the general population and occur in 10% of patients
with peripheral neuropathy. It is important for the clinician to be able to determine whether an
association exists between the paraprotein and the neuropathy. The clinical phenotype of the
neuropathy, as well as the type of monoclonal protein, provides clues for the diagnosis.
Optimal management of paraproteinemic neuropathies requires appropriate evaluation of
the monoclonal protein for an underlying hematologic disorder.
Recent Findings:
Clinical studies in paraproteinemic neuropathies have provided a better understanding of
these disorders, but much is still unknown regarding the pathophysiologic mechanisms.
Recent clinical trials in immunoglobulin M (IgM) neuropathy have shown that better outcome
measures and treatment approaches are needed. Peripheral blood stem cell transplantation
has shown promising improvements in the treatment of polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome
and immunoglobulin light chain (AL) amyloidosis.
Summary:
Recognizing the frequent association of neuropathy with monoclonal proteins and evaluating
for a hematologic malignancy should enable physicians to find better treatments and ultimately
improve neuropathy outcome.

Key Points
& Monoclonal gammopathies are common; incidence is 3.2% in individuals older than
50 years and greater than 5% in those older than 70 years.
& Finding a monoclonal gammopathy in a patient with peripheral neuropathy does not
automatically imply causation.
& Accompanying systemic symptoms raise concern for primary systemic amyloidosis or
POEMS syndrome.
& In cases without an underlying hematologic disorder, a monoclonal protein of the
IgM type is most likely to be associated with a peripheral neuropathy.
& IgM neuropathy typically affects older men and causes a sensory ataxia.
& The electrophysiologic hallmark of IgM neuropathies is typically prolonged distal
latencies implying terminal nerve involvement.
& CIDP with an IgA or IgG monoclonal gammopathy responds to treatment similar to
those without a monoclonal protein.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & The clinical phenotype of the peripheral neuropathy of Waldenström macroglobulinemia
is indistinguishable from IgM monoclonal gammopathy associated neuropathy
(distal acquired demyelinating symmetric neuropathy).
& Treatment-emergent peripheral neuropathy is the most frequent neurologic complication
in patients with multiple myeloma.
& The neuropathy of POEMS syndrome is often mistaken for CIDP.
& A vascular endothelial growth factor level of 200 pg/mL or greater has a specificity
of 95% and sensitivity of 68% in support of POEMS syndrome.
& CIDP that fails to respond to expected immunotherapy should be vigilantly evaluated
for a monoclonal plasma cell proliferative disorder.
& Immunoglobulin light chain amyloidosis typically causes a painful length-dependent
peripheral neuropathy with generalized autonomic failure.
& The most frequent autonomic symptom in immunoglobulin light chain amyloidosis is
orthostatic hypotension.
& Biopsy of the iliac crest bone marrow and abdominal cutaneous fat aspiration will identify
amyloid deposits in 85% of patients with immunoglobulin light chain amyloidosis.

Brachial Plexopathies
Ferrante, Mark A. MD. Continuum (Minneap Minn). October 2014;
20(5 Peripheral Nervous System Disorders): 1323Y1342.

Abstract
Purpose of Review:
The main objective of this article is to offer a regional approach to brachial plexus assessment
because, although the brachial plexus is the largest and most complex peripheral nervous system
structure, most of its disorders involve only a portion of it. Consequently, regional assessment
typically localizes and characterizes the lesion.
Recent Findings:
The sensory axons traversing each region are known and provide localizing information.
Summary:
Because localization dictates the differential diagnosis and the resulting initial clinical
management, examining physicians must first localize the lesion. Localization of a brachial
plexus lesion requires an appreciation of brachial plexus anatomy, lesion classification, and the
routes traversed by the various axons composing the brachial plexus, especially the sensory
axons. This information is reviewed in this article and followed by discussions of several brachial
plexus disorders, especially those with regional predilections.

Key Points
& The brachial plexus supplies the sensory and motor innervation for the entire upper
extremity and most of the shoulder.
& Although most anatomists define the C5 to T1 anterior primary rami as the brachial
plexus roots, most clinicians dealing extensively with brachial plexopathies use a more

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 expanded definition that also includes the C5 to T1 spinal nerves and the dorsal and
ventral roots.
& Because vertical variations in brachial plexus formation do not affect its organization,
they do not affect lesion localization. Thus, lesions localizing to the upper trunk do
so whether the brachial plexus is traditionally composed (C5 to T1), prefixed (C4 to C8),
or postfixed (C6 to T2).
& After the three trunks divide into the six divisions, the segmental nature of the brachial
plexus is lost.
& The posterior cord delivers the C5 dorsal root ganglionYderived sensory axons
(responsible for the C5 dermatome) via the upper and lower lateral brachial cutaneous
nerve branches of the axillary and radial nerves, respectively.
& The brachial plexus is divided anatomically into three plexuses: supraclavicular,
retroclavicular, and infraclavicular. The supraclavicular plexus is further divided into
upper, middle, and lower plexuses. This classification has significant clinical utility
and facilitates interphysician communication.
& Features of proximal brachial plexus involvement, such as Horner syndrome or involvement
of the phrenic, dorsal scapular, or long thoracic nerve, portend a worse prognosis.
& Radiologic features associated with root avulsion include lateral tilt of the cervical spine,
transverse process fracture, and proximal first rib fracture.
& Although MRI is less sensitive than CT myelography for root avulsion, its multiplanar
imaging and tissue-differentiating abilities, lack of radiation and bone-related image
degradation, and its noninvasiveness render it the radiologic procedure of choice for
more distal lesions.
& Because greater force is required to damage both the brachial plexus elements and
the vascular elements, brachial plexus lesions with concomitant vascular injury tend
to have a worse prognosis.
& Because each element of the brachial plexus carries unique sensory and motor axons,
focal plexopathies typically are associated with unique electrodiagnostic features.
& All three portions of the electrodiagnostic examinationYYthe sensory nerve conduction
studies, the motor nerve conduction studies, and the needle EMGYYare performed
because each yields information not provided by the others.
& In addition to differentiating preganglionic and postganglionic lesions, the pattern of
sensory nerve action potential abnormalities has localization utility.
& The temptation to grade severity by fibrillation density must be resisted because it is
more reflective of study timing and, to a lesser extent, the innervation ratio of the muscle
under study.
& With true neurogenic thoracic outlet syndrome, because the band angulates the lower
plexus from below, the T1 axons are affected to a greater extent than the C8 axons. This
produces localizing clinical and electrodiagnostic features that are nearly pathognomonic.
& The presence of a cervical rib is not synonymous with true neurogenic thoracic outlet
syndrome because the incidence of cervical ribs is 20,000 to 80,000 times higher than
that of true neurogenic thoracic outlet syndrome.
& Because the C8 dorsal root ganglion contributes ulnar sensory axons via the C8 anterior
primary ramus, lesions of the C8 anterior primary ramus often mimic an ulnar neuropathy.
& When unrecognized, postYmedian sternotomy plexopathy may be misdiagnosed as an
ulnar neuropathy, potentially leading to an unnecessary surgical procedure and
misdirected blame.
& The motor axon predilection of neuralgic amyotrophy explains why the suprascapular,
long thoracic, axillary, and musculocutaneous nerves are the most frequently affected
proximally and why the motor nerve branches to individual muscles are most affected distally.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Characteristically, the shoulder pain associated with neuralgic amyotrophy is severe
in degree, sudden in onset, maximal within several hours, and located along the lateral
aspect of the shoulder.
& Approximately 75% of neuralgic amyotrophy patients report a preceding trigger. The
delay between the trigger and the onset of pain is less than 1 month and, in over two-thirds
of patients, less than 1 week.
& Accurate diagnosis protects neuralgic amyotrophy patients from unnecessary surgical
procedures and prevents unjustified medical malpractice claims.

Lumbosacral Plexopathy
Dyck, P. James B. MD, FAAN; Thaisetthawatkul, Pariwat MD. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1343Y1358.

Abstract
Purpose of Review:
This article provides an up-to-date review of the clinical features and pathogenesis of different
types of lumbosacral plexopathy and a clinical approach to their evaluation and management.
Often, the pathologic involvement is not limited to the plexus and also involves the root and nerve
levels. These conditions are called lumbosacral radiculoplexus neuropathies.
Recent Findings:
The pathophysiology of diabetic and nondiabetic lumbosacral radiculoplexus neuropathy has
been elucidated; it is ischemic injury due to a perivascular inflammatory process and microvasculitis.
The clinical and neurophysiologic features of these two entities have been found to be similar,
consisting of acute or subacute onset of pain and paresthesia followed by profound motor weakness
asymmetrically involving the lower limbs and associated with weight loss. A lower limb and
motor predominant neuropathy without pain also occurs in diabetes mellitus and has been
shown to be a form of diabetic lumbosacral radiculoplexus neuropathy and not diabetic chronic
inflammatory demyelinating polyradiculoneuropathy (CIDP). The pathophysiology of some cases
of postsurgical lumbosacral plexopathies has recently been shown also to be inflammatory from
microvasculitis, and treatment with immunotherapy in a timely fashion may be desirable.
Summary:
Many pathophysiologic processes, such as neoplastic, traumatic, infectious, radiation, and
inflammatory/microvasculitic processes, can affect the lumbosacral plexus causing lumbosacral
plexopathy. The clinical symptoms and signs depend on the part of the plexus involved and the
temporal course. Management depends on the cause of the lumbosacral plexopathy. Many cases of
lumbosacral plexopathy previously thought to be idiopathic have been shown to be caused by ischemic
injury from microvasculitis; despite lack of evidence for efficacy in improving neurologic deficits,
the authors of this article include immunotherapy in their management of patients with this condition.

Key Points
& Lumbosacral plexopathies arise from various disease processes, such as neoplasm;
infection; trauma; radiation treatment of pelvic neoplasm; hematoma and other
vascular lesions in the retroperitoneal or pelvic areas; mechanical or stretch injury,

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 especially after hip surgery; ischemia; inflammation; infiltration (amyloid); and
idiopathic causes.
& Often, the pathologic involvement of lumbosacral plexopathy is not limited to
the lumbosacral plexus and also involves the root and the nerve levels. These
conditions are not pure lumbosacral plexopathies but are lumbosacral radiculoplexus
neuropathies.
& Most neoplastic causes of lumbosacral plexopathies involve the plexus through direct
spread by local intrapelvic organs (eg, colon, ovaries, cervix, bladder), but in some cases
(prostate), the tumor spreads within the confines of the nerve and spreads longitudinally
(perineurial spread).
& The lumbosacral plexus can be divided into the upper lumbar plexus and the lower
lumbosacral plexus. Each may be affected separately by a local lesion, but a diffuse
lesion usually causes more generalized involvement.
& Pain located in the back, hip, or buttock is often a presenting symptom of neoplastic
lumbosacral plexopathy and usually starts long before the patient develops muscle
weakness or sensory loss.
& Local infection at the psoas muscle or adjacent retroperitoneal space, such as abscess
in the psoas muscle or the gluteal region, can affect the lumbosacral plexus.
& The trauma that causes traumatic lumbosacral plexopathy is usually severe, involves very
high velocity and energy at the time of impact, and is associated with pelvic fractures.
& Late radiation-induced lumbosacral plexopathy can occur many years (up to decades)
after the radiation treatment. A patient usually presents with very slowly progressive
muscle weakness and atrophy with or without sensory loss (which is typically minimal
if present) and usually has no pain in contrast to neoplastic lumbosacral plexopathy.
& Myokymic discharges on needle examination are highly suggestive of a
radiation-induced lumbosacral plexopathy, but their presence does not exclude
recurrent malignancy.
& Retroperitoneal hematoma affecting the psoas muscle can cause lumbosacral plexopathy
and may be related to various causes, either traumatic or nontraumatic, such as
hemophilia, anticoagulant use, or hematologic malignancy.
& The symptoms of diabetic lumbosacral radiculoplexus neuropathy, lumbosacral
radiculoplexus neuropathy, and postsurgical inflammatory neuropathy causing
lumbosacral plexopathy usually consist of acute to subacute onset of severe pain and
paresthesia, followed by motor weakness of proximal and distal segments beginning
focally and unilaterally but progressing bilaterally but asymmetrically. These symptoms
are usually associated with weight loss.
& The pathophysiologic cause of diabetic lumbosacral radiculoplexus neuropathy,
lumbosacral radiculoplexus neuropathy, painless motor and lower limb predominant
diabetic neuropathy, and postsurgical inflammatory neuropathy causing lumbosacral
plexopathy is ischemic injury and microvasculitis.
& One form of diabetic lumbosacral plexopathy presents as painless lower limb and
motor predominant neuropathy. Patients with this form present more slowly and
symmetrically with greater degree of weakness than typical painful diabetic
lumbosacral radiculoplexus neuropathy. Nonetheless, they have diabetic lumbosacral
radiculoplexus neuropathy and not diabetic CIDP.
& Postsurgical inflammatory neuropathies often present as lumbosacral plexopathies,
can occur ipsilaterally or contralaterally to the surgical site, and may be missed because
they are thought to be due to stretch or compressive causes. They are recognized by
neuropathy progression in the postoperative period and confirmed by inflammatory
infiltrates on nerve biopsy.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & The electrophysiologic definition of a lumbosacral plexopathy is involvement of
muscles from at least two lumbosacral root levels from at least two peripheral nerves.
In a pure lumbosacral plexopathy, fibrillation potentials of the lumbosacral paraspinal
muscles are not present, whereas in a lumbosacral radiculoplexus neuropathy, fibrillation
potentials in paraspinal muscles are present.
& Although a controlled trial of IV methylprednisolone did not improve impairments,
it did improve pain and other sensory symptoms in diabetic lumbosacral radiculoplexus
neuropathy, so the authors of this article include corticosteroids in their management
of patients with diabetic lumbosacral radiculoplexus neuropathy, lumbosacral radiculoplexus
neuropathy, and postsurgical inflammatory neuropathy causing lumbosacral plexopathy.

Paraneoplastic Neuropathies
Muppidi, Srikanth MD; Vernino, Steven MD, PhD, FAAN. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1359Y1372.

Abstract
Purpose of Review:
This article provides an approach to the recognition and management of paraneoplastic
neuropathies.
Recent Findings:
Paraneoplastic neuropathies may have unique phenotypic presentations, such as sensory
neuronopathy, autonomic enteric neuropathy, demyelinating neuropathy, and, rarely, motor
neuropathy. Paraneoplastic sensorimotor neuropathy, on the other hand, may be indistinguishable
from other common types of axonal polyneuropathy. Certain patterns of neuropathies are
commonly seen with different types of cancers, but this relationship is not exclusive and not
all patients whose pattern of neuropathy suggests a paraneoplastic disorder have an underlying
cancer. In addition to definitive therapy for malignancy, immunomodulatory therapy, such as
corticosteroids, IV immunoglobulin (IVIg), or immunosuppressants, may benefit some patients,
but there are very few published treatment data for paraneoplastic neuropathies.
Summary:
Prompt recognition of paraneoplastic neuropathies may lead to identification and treatment of an
occult cancer. Treatment can potentially arrest the progression of neuropathy.

Key Points
& Paraneoplastic disorders typically develop prior to the formal diagnosis of cancer,
usually when the malignancy is at a limited stage.
& Prompt treatment of the underlying malignancy could potentially prevent further
worsening or even reverse underlying neuropathy.
& Some patients with paraneoplastic neuropathies are seronegative for diagnostic
antibodies, and, therefore, failure to identify an antibody marker does not exclude
a paraneoplastic neuropathy.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Only about 20% of all cases of sensory neuronopathy are related to an underlying
malignancy. The rest are either idiopathic, associated with autoimmune disorders
(especially Sjögren syndrome), or toxic due to chemotherapy agents.
& In suspected sensory neuronopathy, routine nerve conduction studies will reveal
normal motor responses, with either absent sensory responses or severely diminished
sensory amplitudes.
& Patients with paraneoplastic enteric neuropathy present with severe constipation, nausea,
early satiety due to lack of gastric emptying, abdominal distention, and weight loss.
& In paraneoplastic motor neuropathy, patients present with slowly progressive painless
asymmetric weakness in the limbs. Bulbar involvement is not common, and there
are no upper motor neuron features; these characteristics help differentiate it from
neurodegenerative causes of motor neuron disease (such as ALS).
& It is important to recognize that lymphomas may also cause neuropathy secondary to
direct infiltration of the nerve roots rather than a paraneoplastic phenomenon.
& Since paraneoplastic syndromes are rare, antibody results must be interpreted in the
context of pretest clinical suspicion to reduce the chance of false-positive results leading
to extensive and unnecessary radiologic studies.
& Paraneoplastic antibodies may be directed against cell surface ion channel proteins or
intracellular antigens.
& The most common paraneoplastic antibody found in association with peripheral
neuropathy is anti-Hu antibody.
& Antibodies targeted against cell surface antigens are likely to have a direct role in
altering neuronal function, thus, there is a greater likelihood of improvement in
the paraneoplastic syndrome with immunotherapy. In contrast, antibodies against
intracellular antigens likely reflect the presence of cell-mediated immunity against
the malignancy and the nervous system.
& The most important therapeutic intervention to prevent progression of neuropathy is to
treat the underlying malignancy with the expectation of preventing further progression of
neuropathy.
& Various immunotherapy options have been used in patients with paraneoplastic
neuropathies. These should be considered primarily when patients continue to
worsen after the underlying malignancy has been treated or in patients where there
is no tissue diagnosis of cancer.
& IV immunoglobulin therapy was studied in various open-label studies, but the
effectiveness is difficult to determine because there were no control group comparisons
and IV immunoglobulin was given along with other immunomodulatory therapies.

Autonomic Neuropathies
Sandroni, Paola MD, PhD, FAAN; Iodice, Valeria MD, PhD. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1373Y1396.

Abstract
Purpose of Review:
This article focuses on the most prevalent forms of autonomic neuropathies, but also
discusses conditions such as focal and dysfunctional syndromes (altered autonomic function
in the absence of structural lesions). The goal of this review is to allow the reader to promptly

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

recognize these disorders, identify potentially reversible or treatable causes, and implement the
appropriate treatment as well as supportive care.
Recent Findings:
Secondary forms of autonomic neuropathies (eg, diabetes mellitus, amyloidosis) are much more
common than primary forms, of which autoimmune ganglioneuropathies represent a major
component. However, the spectrum of the latter is continuously evolving and has diagnostic and
therapeutic implications. Testing modalities such as autonomic testing, serum autoimmune
antibody testing, and skin biopsies are becoming more widely available.
Summary:
Autonomic neuropathies are relatively common conditions, and, because of the prognostic
implications as well as impact on patient quality of life, they should be promptly recognized and
treated aggressively. Testing is critical as other conditions may mimic autonomic neuropathies.
Treatment is symptomatic in many cases, but specific therapies are also available in selected
autonomic neuropathies.

Key Points
& Autonomic neuropathies present with wide clinical variation and etiology. Some
have isolated autonomic involvement, and others have concomitant sensory or
motor involvement.
& Autoimmune autonomic ganglionopathy is heterogeneous in severity, distribution of
autonomic failure, and response to treatment.
& Seronegativity does not exclude autoimmune pathogenesis, and treatment with
plasma exchange, IV immunoglobulin, or immunosuppressant agents can be of
benefit in treating seropositive and seronegative patients.
& Autoimmune autonomic neuropathies have a variable presentation and can include
those with focal or restricted autonomic neuropathies with low antibody titers.
& Recognition of and availability of testing for several paraneoplastic antibodies has
prompted a better understanding of immune-mediated paraneoplastic disorders,
including potentially treatable immune-mediated autonomic neuropathies.
& Autonomic involvement is common in diabetes mellitus and increases with disease
duration and severity of hyperglycemia.
& Cardiovascular autonomic neuropathy is an independent factor portending poor
prognosis with increased mortality and risk of sudden death.
& Gastroparesis is the most problematic gastrointestinal symptom in diabetic autonomic
neuropathy and impacts glycemic control due to erratic enteric absorption.
& Patients with diabetes mellitus are also at increased risk for autoimmune autonomic
neuropathies and treatment-induced neuropathy (insulin neuritis).
& The clinical presentation of amyloidosis can be variable, but the major determinant
of prognosis is severity of cardiac involvement.
& Primary amyloidosis due to monoclonal gammopathy, and familial amyloidosis due
to transthyretin mutation, are the most common forms of amyloidosis.
& Stem cell transplant for primary amyloidosis and liver transplant for transthyretin
amyloidosis offer the best treatment options.
& Autonomic dysfunction or failure accompanied by an axonal sensory greater than motor
neuropathy is almost universal in amyloidosis. Its absence should make physicians
question the diagnosis.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Several naturally occurring environmental and industrial toxins and medications can
cause autonomic neuropathy.

Small Fiber Neuropathies

Gibbons, Christopher H. MD, FAAN. Continuum (Minneap Minn). October 2014;
20(5 Peripheral Nervous System Disorders): 1397Y1411.

Abstract
Purpose of Review:
This article reviews the clinical, neurophysiologic, and neuropathologic findings in patients
presenting with small fiber neuropathies. Emphasis is placed on recent updates to the literature,
but also on understanding the differential diagnosis and initial evaluation of patients with
small fiber neuropathy.
Recent Findings:
There have been several updates in the literature about diseases associated with small fiber
neuropathy. First, treatment-induced neuropathy in diabetes mellitus is an iatrogenic small fiber
neuropathy linked to overly rapid correction in blood glucose levels in the setting of chronic
hyperglycemia. Second, several novel mutations to sodium channels have been identified in
patients presenting with idiopathic small fiber neuropathy that may significantly alter our
understanding and future treatment of small fiber neuropathy. Third, antibodies against
voltage-gated potassium channels appear to be associated with a much higher incidence of pain
than would be expected, although the mechanism has not been established. Fourth, the link
between glucose dysregulation, metabolic syndrome, and neuropathy continues to grow. Finally,
several other disorders, including postural tachycardia syndrome, have been postulated to be
associated with small fiber neuropathies.
Summary:
Small fiber neuropathies are a heterogeneous group of disorders that may present with a
variety of sensory or autonomic symptoms. Recent reports highlight a number of new causes
of small fiber neuropathy that continue to reduce the number of remaining idiopathic cases.

Key Points
& Small fiber neuropathies may or may not be painful.
& Small fiber neuropathy is often length dependent, but may present in a patchy or
nonYlength-dependent fashion.
& Small fiber neuropathies can often present with mild paresthesia or no pain at all.
& Typical nerve conduction studies and EMG will not detect a small fiber neuropathy.
& Skin biopsy with immunostaining for protein gene product 9.5 provides the pathologic
gold standard for diagnosis of a small fiber neuropathy.
& Quantitative sensory testing is a widely used research tool, but has not been established as
a standard clinical test.
& Autonomic testing, specifically Quantitative Sudomotor Axon Reflex Testing or
thermoregulatory sweat testing, may provide evidence of a distal small fiber neuropathy.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Treatment-induced neuropathy of diabetes mellitus needs to be considered in any patients
with diabetes mellitus who have an abrupt increase in neuropathic pain or autonomic
dysfunction.
& Selective mutations to the sodium channels are an ongoing area of exciting research, and
clinical testing for mutations may be available over the next few years.
& Fasting blood glucose, 2-hour glucose tolerance testing, and glycosylated hemoglobin
should be checked in patients presenting with a small fiber neuropathy.
& Cholesterol and triglyceride levels should be checked in patients with a small fiber
neuropathy.
& Identifying and treating the underlying disorder is the only method to alter the natural
history of a small fiber neuropathy.

Myasthenia Gravis and Lambert-Eaton

Myasthenic Syndrome
Sanders, Donald B. MD, FAAN; Guptill, Jeffrey T. MD, MA, MHS. Continuum (Minneap Minn).
October 2014; 20(5 Peripheral Nervous System Disorders): 1412Y1424.

Abstract
Purpose of Review:
This article reviews the clinical presentations, diagnostic findings, and treatment options for
autoimmune myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome.
Recent Findings:
Immunologic research is unraveling the immunopathology of MG and identifying targets for
novel immune-based therapy of this condition. MG patients with antibodies to muscle-specific
tyrosine kinase (MuSK) frequently present with symptoms and clinical findings that suggest
nerve or muscle disease.
Summary:
Early diagnosis and treatment have a marked effect on outcome in these diseases. In most cases,
the diagnosis of MG or Lambert-Eaton myasthenic syndrome can be made from the history,
supplemented with directed questions, and a physical examination designed to demonstrate
variable weakness in affected muscle groups. Appropriate confirmatory tests almost always
establish the diagnosis. Although several novel treatment modalities for MG are under
investigation, currently available therapies produce substantial improvement in function and
quality of life in most patients with this condition. Knowledge about the dosing, adverse effects,
and costs of immunomodulatory therapies is essential for the effective management of patients
with MG and Lambert-Eaton myasthenic syndrome.

Key Points
& Myasthenia gravis with acetylcholine receptor antibodies is the most common neuromuscular
junction disorder. It typically presents with fluctuating, fatigable ocular symptoms, and
signs that are frequently ascribed to CNS disease.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 & Muscle-specific tyrosine kinase (MuSK) myasthenia gravis usually affects young females
and may have clinical findings suggestive of nerve or muscle disease. Suspect MuSK
myasthenia gravis if there is isolated head drop, facial muscle or tongue weakness
and atrophy, or weakness that predominates in neck or shoulder muscles.
& Patients and clinicians should be aware of and avoid medications known to exacerbate
myasthenia gravis and Lambert-Eaton myasthenic syndrome weakness.
& Examination of patients with suspected myasthenia gravis should focus on demonstrating
fatigable weakness in affected muscle groups with particular attention to ocular muscles.
Eyelid ptosis that shifts from one eye to the other is virtually diagnostic of myasthenia
gravis. The weakness in myasthenia gravis typically comes and goes and may not be
present during the examination.
& The edrophonium test is positive in 90% of myasthenia gravis patients. Improvement
in lid ptosis, oculomotor weakness, or both are usually produced with 2 mg to 3 mg.
Patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis may become
worse or develop profuse fasciculations after edrophonium.
& Acetylcholine receptor antibodies are present in most myasthenia gravis patients, but
in only about 50% of those with weakness limited to ocular muscles. Consider testing
for muscle-specific tyrosine kinase (MuSK) antibodies if acetylcholine receptor
antibodies are not found and in patients with prominent bulbar, proximal extremity,
or respiratory weakness.
& EMG studies of neuromuscular transmission are most likely to be abnormal in clinically
involved muscles in myasthenia gravis.
& Chest imaging should be performed in patients with myasthenia gravis to exclude
thymoma, which is unlikely unless acetylcholine receptor antibodies are elevated.
& Muscle-specific tyrosine kinase (MuSK) myasthenia gravis patients often require
more aggressive immunosuppression, particularly early in the course of the disease.
Consider rituximab in these patients.
& Lambert-Eaton myasthenic syndrome is characterized by the triad of weakness, dry
mouth, and reduced or absent tendon reflexes. Weakness on examination is frequently
less than the symptoms would suggest.
& Lambert-Eaton myasthenic syndrome patients should have an initial malignancy
workup. If negative, this should be repeated periodically depending on the patient’s
risk of cancer.
& Amifampridine is a mainstay of treatment for patients with Lambert-Eaton myasthenic
syndrome; acetylcholinesterase inhibitors and immunosuppression are usually much
less effective.

* 2014, American Academy of Neurology.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.