3411Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases CHAPTER 437

motor neuron dysfunction and early denervation, typically the first

evidence of the disease is insidiously developing asymmetric weakness,

usually first evident distally in one of the limbs. A detailed history often

discloses recent development of cramping with volitional movements,

typically in the early hours of the morning (e.g., while stretching in

bed). Weakness caused by denervation is associated with progressive

wasting and atrophy of muscles and, particularly early in the illness,

spontaneous twitching of motor units, or fasciculations. In the hands,

a preponderance of extensor over flexor weakness is common. When

the initial denervation involves bulbar rather than limb muscles, the

problem at onset is difficulty with chewing, swallowing, and movements of the face and tongue. Rarely, early involvement of the muscles

of respiration may lead to death before the disease is far advanced

TABLE 437-1 Etiology of Motor Neuron Disorders

DIAGNOSTIC CATEGORY INVESTIGATION

Structural lesions

 Parasagittal or foramen magnum

tumors

Cervical spondylosis

Chiari malformation of syrinx

 Spinal cord arteriovenous

malformation

MRI scan of head (including foramen

magnum and cervical spine)

Infections

Bacterial—tetanus, Lyme

Viral—poliomyelitis, herpes zoster

Retroviral—myelopathy

CSF exam, culture

Lyme titer

Antiviral antibody

HTLV-1 titers

Intoxications, physical agents

Toxins—lead, aluminum, others

Drugs—strychnine, phenytoin

Electric short, x-irradiation

24-h urine for heavy metals

Serum lead level

Immunologic mechanisms

Plasma cell dyscrasias

Autoimmune polyradiculopathy

 Motor neuropathy with conduction

block

Paraneoplastic

Paracarcinomatous

Complete blood counta

Sedimentation ratea

Total proteina

Anti-GM1 antibodiesa

Anti-Hu antibody

MRI scan, bone marrow biopsy

Metabolic

Hypoglycemia

Hyperparathyroidism

Hyperthyroidism

 Deficiency of folate, vitamin B12,

vitamin E

Malabsorption

Deficiency of copper, zinc

Mitochondrial dysfunction

Fasting blood sugara

Routine chemistries including calciuma

PTH

Thyroid functiona

Vitamin B12, vitamin E, folatea

Serum zinc, coppera

24-h stool fat, carotene, prothrombin

time

Fasting lactate, pyruvate, ammonia

Hyperlipidemia Lipid electrophoresis

Hyperglycinuria Urine and serum amino acids

CSF amino acids

Hereditary disorders

C9orf72

Superoxide dismutase

TDP43

FUS/TLS

Androgen receptor defect

(Kennedy’s disease)

WBC or cheek swab DNA for

mutational analysis

a

Should be obtained in all cases.

Abbreviations: CSF, cerebrospinal fluid; FUS/TLS, fused in sarcoma/translocated in

liposarcoma; HTLV-1, human T-cell lymphotropic virus; MRI, magnetic resonance

imaging; PTH, parathyroid; WBC, white blood cell.

in nonmotor systems. Moreover, studies of glucose metabolism in the

illness also indicate that there is neuronal dysfunction outside of the

motor system. Pathologic studies reveal proliferation of microglial cells

and astrocytes in affected regions; in some cases, this phenomenon,

designated neuroinflamation, can be visualized using positron emission tomography (PET) scanning for ligands that are recognized by

activated microglia. Within the motor system, there is some selectivity

of involvement. Thus, motor neurons required for ocular motility

remain unaffected, as do the parasympathetic neurons in the sacral

spinal cord (the nucleus of Onufrowicz, or Onuf) that innervate the

sphincters of the bowel and bladder.

■ CLINICAL MANIFESTATIONS

The manifestations of ALS are somewhat variable depending on

whether corticospinal neurons or lower motor neurons in the brainstem and spinal cord are more prominently involved. With lower

TABLE 437-2 Sporadic Motor Neuron Diseases

CHRONIC ENTITY

Upper and lower motor neuron Amyotrophic lateral sclerosis

Predominantly upper motor neuron Primary lateral sclerosis

Predominantly lower motor neuron Multifocal motor neuropathy with

conduction block

Motor neuropathy with

paraproteinemia or cancer

Motor predominant peripheral

neuropathies

OTHER

Associated with other

neurodegenerative disorders

Secondary motor neuron disorders

(see Table 437-1)

ACUTE

Poliomyelitis

Herpes zoster

Coxsackie virus

West Nile virus

FIGURE 437-1 Amyotrophic lateral sclerosis. Axial T2-weighted magnetic

resonance imaging (MRI) scan through the lateral ventricles of the brain reveals

abnormal high signal intensity within the corticospinal tracts (arrows). This MRI

feature represents an increase in water content in myelin tracts undergoing

Wallerian degeneration secondary to cortical motor neuronal loss. This finding is

commonly present in ALS but can also be seen in AIDS-related encephalopathy,

infarction, or other disease processes that produce corticospinal neuronal loss in

a symmetric fashion.

3412 PART 13 Neurologic Disorders

elsewhere. With prominent corticospinal involvement, there is hyperactivity of the muscle-stretch reflexes (tendon jerks) and, often, spastic

resistance to passive movements of the affected limbs. Patients with

significant reflex hyperactivity complain of muscle stiffness often out of

proportion to weakness. Degeneration of the corticobulbar projections

innervating the brainstem results in dysarthria and exaggeration of the

motor expressions of emotion. The latter leads to involuntary excess in

weeping or laughing (pseudobulbar affect).

Virtually any muscle group may be the first to show signs of disease, but, as time passes, more and more muscles become involved

until ultimately the disorder takes on a symmetric distribution in all

regions. It is characteristic of ALS that, regardless of whether the initial

disease involves upper or lower motor neurons, both will eventually

be implicated. Even in the late stages of the illness, sensory, bowel and

bladder, and cognitive functions are preserved. Even when there is

severe brainstem disease, ocular motility is spared until the very late

stages of the illness. As noted, in some cases (particularly those that are

familial), ALS develops concurrently with frontotemporal dementia,

characterized by early behavioral abnormalities with prominent behavioral features indicative of frontal lobe dysfunction.

A committee of the World Federation of Neurology has established

diagnostic guidelines for ALS. Essential for the diagnosis is simultaneous upper and lower motor neuron involvement with progressive

weakness and the exclusion of all alternative diagnoses. The disorder

is ranked as “definite” ALS when three or four of the following are

involved: bulbar, cervical, thoracic, and lumbosacral motor neurons.

When two sites are involved, the diagnosis is “probable,” and when

only one site is implicated, the diagnosis is “possible.” An exception is

made for those who have progressive upper and lower motor neuron

signs at only one site and a mutation in the gene encoding superoxide

dismutase (SOD1; see below).

It is now recognized that another clinical manifestation in most

cases of ALS is the presence in cerebrospinal fluid (CSF) of markers

of neurodegeneration, such as elevated levels of neurofilament light

chains or phosphorylated neurofilament heavy chains; some markers

of inflammation (e.g., monocyte chemoattractant protein 1) are also

elevated. These CSF biomarkers are increasingly used as endpoints in

clinical trials.

■ EPIDEMIOLOGY

The illness is relentlessly progressive, leading to death from respiratory

paralysis; the median survival is from 3 to 5 years. There are very rare

reports of stabilization or even regression of ALS. In most societies,

there is an incidence of 1–3 per 100,000 and a prevalence of 3–5 per

100,000. It is striking that at least 1 in 1000 deaths in North America

and Western Europe (and probably elsewhere) are due to ALS; this

finding predicts that more than 300,000 individuals now alive in the

United States will die of ALS. Several endemic foci of higher prevalence

exist in the western Pacific (e.g., in specific regions of Guam or Papua

New Guinea). In the United States and Europe, men are somewhat

more frequently affected than women. Epidemiologic studies have

incriminated risk factors for this disease including exposure to pesticides and insecticides, silica, smoking, and possibly service in the

military. Although ALS is overwhelmingly a sporadic disorder, some

10% of cases are inherited as an autosomal dominant trait.

■ FAMILIAL ALS

Several forms of selective motor neuron disease are inheritable

(Table 437-3). Familial ALS (FALS) involves both corticospinal and

lower motor neurons. Apart from its inheritance as an autosomal dominant trait, it is clinically indistinguishable from sporadic ALS. Genetic

studies have identified mutations in multiple genes, including those

encoding the protein C9orf72 (open reading frame 72 on chromosome

9), cytosolic enzyme SOD1 (superoxide dismutase), the RNA binding

proteins TDP43 (encoded by the TAR DNA binding protein gene), and

fused in sarcoma/translocated in liposarcoma (FUS/TLS), as the most

common causes of FALS. Mutations in C9orf72 account for ~45–50%

of FALS and perhaps 5–10% of sporadic ALS cases. Mutations in SOD1

explain another 20% of cases of FALS, whereas TDP43 and FUS/TLS

each represent about 5% of familial cases. Mutations in several other

genes (such as optineurin, TBK1 and profilin-1) each cause about ~1%

of cases.

Rare mutations in other genes are also clearly implicated in ALS-like

diseases. Thus, a familial, dominantly inherited motor disorder that

in some individuals closely mimics the ALS phenotype arises from

mutations in a gene that encodes a vesicle-binding protein. Mutations

in senataxin, a helicase, cause an early-adult-onset, slowly evolving

ALS variant. Kennedy’s syndrome is an X-linked, adult-onset disorder

that may mimic ALS, as described below. Tau gene mutations usually

underlie frontotemporal dementia, but in some instances may be associated with prominent motor neuron findings.

Genetic analyses are also beginning to illuminate the pathogenesis

of some childhood-onset motor neuron diseases. For example, a slowly

disabling degenerative, predominantly upper motor neuron disease

that starts in the first decade is caused by mutations in a gene that

expresses a novel signaling molecule with properties of a guanineexchange factor, termed alsin.

■ DIFFERENTIAL DIAGNOSIS

Because ALS is currently untreatable, it is imperative that potentially

remediable causes of motor neuron dysfunction be excluded (Table

437-1). This is particularly true in cases that are atypical by virtue of

(1) restriction to either upper or lower motor neurons, (2) involvement

of neurons other than motor neurons, and (3) evidence of motor neuronal conduction block on electrophysiologic testing. Compression

of the cervical spinal cord or cervicomedullary junction from tumors

in the cervical regions or at the foramen magnum or from cervical

spondylosis with osteophytes projecting into the vertebral canal can

produce weakness, wasting, and fasciculations in the upper limbs and

spasticity in the legs, closely resembling ALS. The absence of cranial

nerve involvement may be helpful in differentiation, although some

foramen magnum lesions may compress the twelfth cranial (hypoglossal) nerve, with resulting paralysis of the tongue. Absence of pain

or of sensory changes, normal bowel and bladder function, normal

radiologic studies of the spine, and normal CSF all favor ALS. Where

doubt exists, MRI scans and possibly contrast myelography should be

performed to visualize the cervical spinal cord.

Another important entity in the differential diagnosis of ALS is

multifocal motor neuropathy with conduction block (MMCB), discussed

below. A diffuse, lower motor axonal neuropathy mimicking ALS

sometimes evolves in association with hematopoietic disorders such as

lymphoma or multiple myeloma. In this clinical setting, the presence

of an M-component in serum should prompt consideration of a bone

marrow biopsy. Lyme disease (Chap. 186) may also cause an axonal,

lower motor neuropathy, although typically with intense proximal limb

pain and a CSF pleocytosis.

Other treatable disorders that occasionally mimic ALS are chronic

lead poisoning and thyrotoxicosis. These disorders may be suggested

by the patient’s social or occupational history or by unusual clinical

features. When the family history is positive, disorders involving the

genes encoding C9orf72, cytosolic SOD1, TDP43, FUS/TLS, and

adult hexosaminidase A or α-glucosidase deficiency must be excluded

(Chap. 418). These are readily identified by appropriate laboratory

tests; importantly, panels for simultaneous analysis of multiple ALS and

FTD genes are now commercially available. Benign fasciculations are

occasionally a source of concern because on inspection they resemble

the fascicular twitchings that accompany motor neuron degeneration.

The absence of weakness, atrophy, or denervation phenomena on

electrophysiologic examination usually excludes ALS or other serious

neurologic disease. Patients who have recovered from poliomyelitis may

experience a delayed deterioration of motor neurons that presents clinically with progressive weakness, atrophy, and fasciculations. Its cause

is unknown, but it is thought to reflect sublethal prior injury to motor

neurons by poliovirus (Chap. 204).

Rarely, ALS develops concurrently with features indicative of more

widespread neurodegeneration. Thus, one infrequently encounters

3413Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases CHAPTER 437

TABLE 437-3 Selected Genetic Motor Neuron Diseases

DISEASE

GENE

SYMBOL GENE NAME INHERITANCE

FREQUENCY

(IN THE UNITED

STATES) USUAL ONSET

PROTEIN

FUNCTION UNUSUAL FEATURES

I. Upper and Lower Motor Neurons (Familial ALS)

ALS1 SOD1 Cu/Zn superoxide

dismutase 1

AD 20% FALS Adult Protein

antioxidant

ALS2 ALS2 Alsin AR <1% FALS Juvenile GEF signaling Severe corticobulbar,

corticospinal features

may mimic PLS;

childhood onset

ALS4 SETX Senataxin AD ~1% FALS Late juvenile DNA helicase Late-childhood onset

ALS6 FUS/TLS Fused in sarcoma/

translocated in

liposarcoma

AD 5% FALS Adult DNA, RNA

binding

ALS8/SMA VAPB Vesicle-associated

protein B

AD <1% Adult Vesicular

trafficking

ALS10 TARDBP TAR DNA binding protein AD 5% FALS Adult DNA, RNA

binding

ALS12 OPTN Optineurin AD/AR ~1% FALS Adult Attenuates NF-κB

ALS14 VCP Valosin-containing

protein

AD ~ 1% FALS Adult ATPase

ALS18 PFN1 Profilin 1 AD ~1% FALS Adult Involved in actin

polymerization

ALS20 HNRNPA1 Heterogeneous nuclear

ribonucleoprotein A1

AD <1% Adult Heteronuclear

RNA binding

protein

ALS DCTN1 Dynactin AD <1% Adult Axonal transport May cause vocal cord

paralysis or PLSe

ALS-FTD TBK1 Tank-binding kinase 1 AD Adult NF-κB signaling Also mimics PLS

ALS-FTD UBQLN2 Ubiquilin 2 X-LD <1% Adult or

juvenile

Protein

degradation

ALS-FTD CHMP2B Chromatin-modifying

protein 2B

AD <1% FALS Adult Chromatinbinding protein

ALS-FTD C9ORF72 Chromosome 9 open

reading frame 72

AD 40–50% FALS Adult Regulates vesicle

trafficking

May also be associated

with parkinsonism, PLS

ALS-FTD MAPT Microtubule-associated

protein Tau

AD Adult Cytoskeletal

protein

Usually causes only FTD

II. Lower Motor Neurons

Spinal muscular

atrophies

SMN Survival motor neuron AR 1/10,000 live

births

Infancy RNA metabolism

GM2-gangliosidosis

1. Sandhoff’s disease HEXB Hexosaminidase B AR Childhood Ganglioside

recycling

2. AB variant GM2A GM2-activator protein AR Childhood Ganglioside

recycling

 3. Adult Tay-Sachs

disease

HEXA Hexosaminidase A AR Childhood Ganglioside

recycling

X-linked spinobulbar

muscular atrophy

AR Androgen receptor XR Adult Nuclear signaling

III. Upper Motor Neuron (Selected HSPs)

SPG3A ATL1 Atlastin AD 10% AD FSP Childhood GTPase—vesicle

recycling

SPG4 SPAST Spastin AD 50–60% AD FSP Early adulthood ATPase family—

microtubule

associate

Some sensory loss

SPG6 NIPA1 Nonimprinted in

Prader-Willi/Angelman

syndrome 1

AD Early adulthood Membrane

transporter or

receptor

Deleted in Prader-Willi,

Angelman’s

SPG8 WASHC5 Strumpellin AD Early adulthood Ubiquitous,

spectrin-like

SPG10 KIF5A Kinesin heavy-chain

isoform 5A

AD 10% AD FSP Second–third

decade

Motor-associated

protein

± Peripheral neuropathy,

retardation

SPG31 REEP1 Receptor expression

enhancing protein 1

AD 10% AD FSP Early Mitochondrial

protein

Rarely, amyotrophy

(Continued)

3414 PART 13 Neurologic Disorders

otherwise-typical ALS patients with a parkinsonian movement disorder or frontotemporal dementia, particularly in instances of C9orf72

mutations, which strongly suggests that the simultaneous occurrence

of two disorders is a direct consequence of the gene mutation. As

another example, prominent amyotrophy has been described as a dominantly inherited disorder in individuals with bizarre behavior and a

movement disorder suggestive of parkinsonism; many such cases have

now been ascribed to mutations that alter the expression of tau protein

in the brain (Chap. 432). In other cases, ALS develops simultaneously

with a striking frontotemporal dementia. An ALS-like disorder has also

been described in some individuals with chronic traumatic encephalopathy, associated with deposition of TDP43 and neurofibrillary

tangles in motor neurons.

■ PATHOGENESIS

The cause of sporadic ALS is not well defined. Several mechanisms

that impair motor neuron viability have been elucidated in rodents

induced to develop motor neuron disease by SOD1 or profilin-1

transgenes with ALS-associated mutations. One may loosely group

the genetic causes of ALS into three categories. In one group, the

primary problem is inherent instability of the mutant proteins, with

subsequent perturbations in protein degradation (SOD1, ubiquilin-1

and 2, p62). In the second category, the causative mutant genes perturb RNA processing, transport, and metabolism (C9orf73, TDP43,

FUS). In the case of C9orf72, the molecular pathology is an expansion

of an intronic hexanucleotide repeat (-GGGGCC-) beyond an upper

normal of 30 repeats to hundreds or even thousands of repeats. As

observed in other intronic repeat disorders such as myotonic dystrophy (Chap. 449) and spinocerebellar atrophy type 8 (Chap. 439), the

expanded intronic repeats generate expanded RNA repeats that form

intranuclear foci and may confer toxicity by sequestering transcription

factors or by undergoing noncanonical protein translation across all

possible reading frames of the expanded RNA tracts. Importantly,

the latter process generates lengthy dipeptides that are detected in

the spinal fluid and are a unique biomarker for C9orf72 ALS. TDP43

and FUS are multifunctional proteins that bind RNA and DNA and

shuttle between the nucleus and the cytoplasm, playing multiple roles

in the control of cell proliferation, DNA repair and transcription,

and gene translation, both in the cytoplasm and locally in dendritic

spines in response to electrical activity. How mutations in FUS/TLS

provoke motor neuron cell death is not clear, although this may represent loss of function of FUS/TLS in the nucleus or an acquired, toxic

function of the mutant proteins in the cytosol. In the third group of

ALS genes, the primary problem is defective axonal cytoskeleton and

transport (dynactin, profilin-1). It is striking that variants in other

genes influence survival in ALS but not ALS susceptibility. Intermediate-length polyglutamine-coding expansions (-CAG-) in the gene

ataxin-2 confer increased ALS susceptibility; suppression of ataxin-2

expression extends survival in transgenic ALS mice and is the basis for

clinical trials of ataxin-2 suppression. Beyond the upstream, primary

defects, it is also evident that the ultimate neuronal cell death process

is complex, involving multiple cellular processes acting in diverse

components of the motor neuron (dendrites, cell body, axons, neuromuscular junction) to accelerate cell death. These include but are not

limited to excitotoxicity, defective autophagy, impairment of axonal

transport, oxidative stress, activation of endoplasmic reticulum stress

and the unfolded protein response, and mitochondrial dysfunction.

As well, the hexanucleotide expansions that cause C9orf72 ALS disrupt

nucleocytoplasmic transport; the importance of this observation is

underscored by the finding that mutations in the gene encoding GLE1,

a protein that mediates mRNA export, cause an aggressive, infantile

motor neuron disease.

Multiple studies have convincingly demonstrated that proliferating,

activated nonneuronal cells such as microglia and astrocytes importantly influence the disease course, at least in ALS-transgenic mice. A

striking additional finding in ALS and most neurodegenerative disorders is that miscreant proteins arising from gene defects in familial

forms of these diseases are often implicated in sporadic forms of the

same disorder. For example, some reports propose that nonheritable,

posttranslational modifications in SOD1 are pathogenic in sporadic

ALS; indeed, SOD1 aggregates are sometimes observed in spinal cord

in sporadic ALS without SOD1 mutations. Germline mutations in the

genes encoding β-amyloid and α-synuclein cause familial forms of Alzheimer’s and Parkinson’s diseases, and posttranslational, noninherited

abnormalities in these proteins are also central to sporadic Alzheimer’s

and Parkinson’s diseases.

TABLE 437-3 Selected Genetic Motor Neuron Diseases

DISEASE

GENE

SYMBOL GENE NAME INHERITANCE

FREQUENCY

(IN THE UNITED

STATES) USUAL ONSET

PROTEIN

FUNCTION UNUSUAL FEATURES

3412 PART 13 Neurologic Disorders

elsewhere. With prominent corticospinal involvement, there is hyperactivity of the muscle-stretch reflexes (tendon jerks) and, often, spastic

resistance to passive movements of the affected limbs. Patients with

significant reflex hyperactivity complain of muscle stiffness often out of

proportion to weakness. Degeneration of the corticobulbar projections

innervating the brainstem results in dysarthria and exaggeration of the

motor expressions of emotion. The latter leads to involuntary excess in

weeping or laughing (pseudobulbar affect).

Virtually any muscle group may be the first to show signs of disease, but, as time passes, more and more muscles become involved

until ultimately the disorder takes on a symmetric distribution in all

regions. It is characteristic of ALS that, regardless of whether the initial

disease involves upper or lower motor neurons, both will eventually

be implicated. Even in the late stages of the illness, sensory, bowel and

bladder, and cognitive functions are preserved. Even when there is

severe brainstem disease, ocular motility is spared until the very late

stages of the illness. As noted, in some cases (particularly those that are

familial), ALS develops concurrently with frontotemporal dementia,

characterized by early behavioral abnormalities with prominent behavioral features indicative of frontal lobe dysfunction.

A committee of the World Federation of Neurology has established

diagnostic guidelines for ALS. Essential for the diagnosis is simultaneous upper and lower motor neuron involvement with progressive

weakness and the exclusion of all alternative diagnoses. The disorder

is ranked as “definite” ALS when three or four of the following are

involved: bulbar, cervical, thoracic, and lumbosacral motor neurons.

When two sites are involved, the diagnosis is “probable,” and when

only one site is implicated, the diagnosis is “possible.” An exception is

made for those who have progressive upper and lower motor neuron

signs at only one site and a mutation in the gene encoding superoxide

dismutase (SOD1; see below).

It is now recognized that another clinical manifestation in most

cases of ALS is the presence in cerebrospinal fluid (CSF) of markers

of neurodegeneration, such as elevated levels of neurofilament light

chains or phosphorylated neurofilament heavy chains; some markers

of inflammation (e.g., monocyte chemoattractant protein 1) are also

elevated. These CSF biomarkers are increasingly used as endpoints in

clinical trials.

■ EPIDEMIOLOGY

The illness is relentlessly progressive, leading to death from respiratory

paralysis; the median survival is from 3 to 5 years. There are very rare

reports of stabilization or even regression of ALS. In most societies,

there is an incidence of 1–3 per 100,000 and a prevalence of 3–5 per

100,000. It is striking that at least 1 in 1000 deaths in North America

and Western Europe (and probably elsewhere) are due to ALS; this

finding predicts that more than 300,000 individuals now alive in the

United States will die of ALS. Several endemic foci of higher prevalence

exist in the western Pacific (e.g., in specific regions of Guam or Papua

New Guinea). In the United States and Europe, men are somewhat

more frequently affected than women. Epidemiologic studies have

incriminated risk factors for this disease including exposure to pesticides and insecticides, silica, smoking, and possibly service in the

military. Although ALS is overwhelmingly a sporadic disorder, some

10% of cases are inherited as an autosomal dominant trait.

■ FAMILIAL ALS

Several forms of selective motor neuron disease are inheritable

(Table 437-3). Familial ALS (FALS) involves both corticospinal and

lower motor neurons. Apart from its inheritance as an autosomal dominant trait, it is clinically indistinguishable from sporadic ALS. Genetic

studies have identified mutations in multiple genes, including those

encoding the protein C9orf72 (open reading frame 72 on chromosome

9), cytosolic enzyme SOD1 (superoxide dismutase), the RNA binding

proteins TDP43 (encoded by the TAR DNA binding protein gene), and

fused in sarcoma/translocated in liposarcoma (FUS/TLS), as the most

common causes of FALS. Mutations in C9orf72 account for ~45–50%

of FALS and perhaps 5–10% of sporadic ALS cases. Mutations in SOD1

explain another 20% of cases of FALS, whereas TDP43 and FUS/TLS

each represent about 5% of familial cases. Mutations in several other

genes (such as optineurin, TBK1 and profilin-1) each cause about ~1%

of cases.

Rare mutations in other genes are also clearly implicated in ALS-like

diseases. Thus, a familial, dominantly inherited motor disorder that

in some individuals closely mimics the ALS phenotype arises from

mutations in a gene that encodes a vesicle-binding protein. Mutations

in senataxin, a helicase, cause an early-adult-onset, slowly evolving

ALS variant. Kennedy’s syndrome is an X-linked, adult-onset disorder

that may mimic ALS, as described below. Tau gene mutations usually

underlie frontotemporal dementia, but in some instances may be associated with prominent motor neuron findings.

Genetic analyses are also beginning to illuminate the pathogenesis

of some childhood-onset motor neuron diseases. For example, a slowly

disabling degenerative, predominantly upper motor neuron disease

that starts in the first decade is caused by mutations in a gene that

expresses a novel signaling molecule with properties of a guanineexchange factor, termed alsin.

■ DIFFERENTIAL DIAGNOSIS

Because ALS is currently untreatable, it is imperative that potentially

remediable causes of motor neuron dysfunction be excluded (Table

437-1). This is particularly true in cases that are atypical by virtue of

(1) restriction to either upper or lower motor neurons, (2) involvement

of neurons other than motor neurons, and (3) evidence of motor neuronal conduction block on electrophysiologic testing. Compression

of the cervical spinal cord or cervicomedullary junction from tumors

in the cervical regions or at the foramen magnum or from cervical

spondylosis with osteophytes projecting into the vertebral canal can

produce weakness, wasting, and fasciculations in the upper limbs and

spasticity in the legs, closely resembling ALS. The absence of cranial

nerve involvement may be helpful in differentiation, although some

foramen magnum lesions may compress the twelfth cranial (hypoglossal) nerve, with resulting paralysis of the tongue. Absence of pain

or of sensory changes, normal bowel and bladder function, normal

radiologic studies of the spine, and normal CSF all favor ALS. Where

doubt exists, MRI scans and possibly contrast myelography should be

performed to visualize the cervical spinal cord.

Another important entity in the differential diagnosis of ALS is

multifocal motor neuropathy with conduction block (MMCB), discussed

below. A diffuse, lower motor axonal neuropathy mimicking ALS

sometimes evolves in association with hematopoietic disorders such as

lymphoma or multiple myeloma. In this clinical setting, the presence

of an M-component in serum should prompt consideration of a bone

marrow biopsy. Lyme disease (Chap. 186) may also cause an axonal,

lower motor neuropathy, although typically with intense proximal limb

pain and a CSF pleocytosis.

Other treatable disorders that occasionally mimic ALS are chronic

lead poisoning and thyrotoxicosis. These disorders may be suggested

by the patient’s social or occupational history or by unusual clinical

features. When the family history is positive, disorders involving the

genes encoding C9orf72, cytosolic SOD1, TDP43, FUS/TLS, and

adult hexosaminidase A or α-glucosidase deficiency must be excluded

(Chap. 418). These are readily identified by appropriate laboratory

tests; importantly, panels for simultaneous analysis of multiple ALS and

FTD genes are now commercially available. Benign fasciculations are

occasionally a source of concern because on inspection they resemble

the fascicular twitchings that accompany motor neuron degeneration.

The absence of weakness, atrophy, or denervation phenomena on

electrophysiologic examination usually excludes ALS or other serious

neurologic disease. Patients who have recovered from poliomyelitis may

experience a delayed deterioration of motor neurons that presents clinically with progressive weakness, atrophy, and fasciculations. Its cause

is unknown, but it is thought to reflect sublethal prior injury to motor

neurons by poliovirus (Chap. 204).

Rarely, ALS develops concurrently with features indicative of more

widespread neurodegeneration. Thus, one infrequently encounters

3413Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases CHAPTER 437

TABLE 437-3 Selected Genetic Motor Neuron Diseases

DISEASE

GENE

SYMBOL GENE NAME INHERITANCE

FREQUENCY

(IN THE UNITED

STATES) USUAL ONSET

PROTEIN

FUNCTION UNUSUAL FEATURES

I. Upper and Lower Motor Neurons (Familial ALS)

ALS1 SOD1 Cu/Zn superoxide

dismutase 1

AD 20% FALS Adult Protein

antioxidant

ALS2 ALS2 Alsin AR <1% FALS Juvenile GEF signaling Severe corticobulbar,

corticospinal features

may mimic PLS;

childhood onset

ALS4 SETX Senataxin AD ~1% FALS Late juvenile DNA helicase Late-childhood onset

ALS6 FUS/TLS Fused in sarcoma/

translocated in

liposarcoma

AD 5% FALS Adult DNA, RNA

binding

ALS8/SMA VAPB Vesicle-associated

protein B

AD <1% Adult Vesicular

trafficking

ALS10 TARDBP TAR DNA binding protein AD 5% FALS Adult DNA, RNA

binding

ALS12 OPTN Optineurin AD/AR ~1% FALS Adult Attenuates NF-κB

ALS14 VCP Valosin-containing

protein

AD ~ 1% FALS Adult ATPase

ALS18 PFN1 Profilin 1 AD ~1% FALS Adult Involved in actin

polymerization

ALS20 HNRNPA1 Heterogeneous nuclear

ribonucleoprotein A1

AD <1% Adult Heteronuclear

RNA binding

protein

ALS DCTN1 Dynactin AD <1% Adult Axonal transport May cause vocal cord

paralysis or PLSe

ALS-FTD TBK1 Tank-binding kinase 1 AD Adult NF-κB signaling Also mimics PLS

ALS-FTD UBQLN2 Ubiquilin 2 X-LD <1% Adult or

juvenile

Protein

degradation

ALS-FTD CHMP2B Chromatin-modifying

protein 2B

AD <1% FALS Adult Chromatinbinding protein

ALS-FTD C9ORF72 Chromosome 9 open

reading frame 72

AD 40–50% FALS Adult Regulates vesicle

trafficking

May also be associated

with parkinsonism, PLS

ALS-FTD MAPT Microtubule-associated

protein Tau

AD Adult Cytoskeletal

protein

Usually causes only FTD

II. Lower Motor Neurons

Spinal muscular

atrophies

SMN Survival motor neuron AR 1/10,000 live

births

Infancy RNA metabolism

GM2-gangliosidosis

1. Sandhoff’s disease HEXB Hexosaminidase B AR Childhood Ganglioside

recycling

2. AB variant GM2A GM2-activator protein AR Childhood Ganglioside

recycling

 3. Adult Tay-Sachs

disease

HEXA Hexosaminidase A AR Childhood Ganglioside

recycling

X-linked spinobulbar

muscular atrophy

AR Androgen receptor XR Adult Nuclear signaling

III. Upper Motor Neuron (Selected HSPs)

SPG3A ATL1 Atlastin AD 10% AD FSP Childhood GTPase—vesicle

recycling

SPG4 SPAST Spastin AD 50–60% AD FSP Early adulthood ATPase family—

microtubule

associate

Some sensory loss

SPG6 NIPA1 Nonimprinted in

Prader-Willi/Angelman

syndrome 1

AD Early adulthood Membrane

transporter or

receptor

Deleted in Prader-Willi,

Angelman’s

SPG8 WASHC5 Strumpellin AD Early adulthood Ubiquitous,

spectrin-like

SPG10 KIF5A Kinesin heavy-chain

isoform 5A

AD 10% AD FSP Second–third

decade

Motor-associated

protein

± Peripheral neuropathy,

retardation

SPG31 REEP1 Receptor expression

enhancing protein 1

AD 10% AD FSP Early Mitochondrial

protein

Rarely, amyotrophy

(Continued)

3414 PART 13 Neurologic Disorders

otherwise-typical ALS patients with a parkinsonian movement disorder or frontotemporal dementia, particularly in instances of C9orf72

mutations, which strongly suggests that the simultaneous occurrence

of two disorders is a direct consequence of the gene mutation. As

another example, prominent amyotrophy has been described as a dominantly inherited disorder in individuals with bizarre behavior and a

movement disorder suggestive of parkinsonism; many such cases have

now been ascribed to mutations that alter the expression of tau protein

in the brain (Chap. 432). In other cases, ALS develops simultaneously

with a striking frontotemporal dementia. An ALS-like disorder has also

been described in some individuals with chronic traumatic encephalopathy, associated with deposition of TDP43 and neurofibrillary

tangles in motor neurons.

■ PATHOGENESIS

The cause of sporadic ALS is not well defined. Several mechanisms

that impair motor neuron viability have been elucidated in rodents

induced to develop motor neuron disease by SOD1 or profilin-1

transgenes with ALS-associated mutations. One may loosely group

the genetic causes of ALS into three categories. In one group, the

primary problem is inherent instability of the mutant proteins, with

subsequent perturbations in protein degradation (SOD1, ubiquilin-1

and 2, p62). In the second category, the causative mutant genes perturb RNA processing, transport, and metabolism (C9orf73, TDP43,

FUS). In the case of C9orf72, the molecular pathology is an expansion

of an intronic hexanucleotide repeat (-GGGGCC-) beyond an upper

normal of 30 repeats to hundreds or even thousands of repeats. As

observed in other intronic repeat disorders such as myotonic dystrophy (Chap. 449) and spinocerebellar atrophy type 8 (Chap. 439), the

expanded intronic repeats generate expanded RNA repeats that form

intranuclear foci and may confer toxicity by sequestering transcription

factors or by undergoing noncanonical protein translation across all

possible reading frames of the expanded RNA tracts. Importantly,

the latter process generates lengthy dipeptides that are detected in

the spinal fluid and are a unique biomarker for C9orf72 ALS. TDP43

and FUS are multifunctional proteins that bind RNA and DNA and

shuttle between the nucleus and the cytoplasm, playing multiple roles

in the control of cell proliferation, DNA repair and transcription,

and gene translation, both in the cytoplasm and locally in dendritic

spines in response to electrical activity. How mutations in FUS/TLS

provoke motor neuron cell death is not clear, although this may represent loss of function of FUS/TLS in the nucleus or an acquired, toxic

function of the mutant proteins in the cytosol. In the third group of

ALS genes, the primary problem is defective axonal cytoskeleton and

transport (dynactin, profilin-1). It is striking that variants in other

genes influence survival in ALS but not ALS susceptibility. Intermediate-length polyglutamine-coding expansions (-CAG-) in the gene

ataxin-2 confer increased ALS susceptibility; suppression of ataxin-2

expression extends survival in transgenic ALS mice and is the basis for

clinical trials of ataxin-2 suppression. Beyond the upstream, primary

defects, it is also evident that the ultimate neuronal cell death process

is complex, involving multiple cellular processes acting in diverse

components of the motor neuron (dendrites, cell body, axons, neuromuscular junction) to accelerate cell death. These include but are not

limited to excitotoxicity, defective autophagy, impairment of axonal

transport, oxidative stress, activation of endoplasmic reticulum stress

and the unfolded protein response, and mitochondrial dysfunction.

As well, the hexanucleotide expansions that cause C9orf72 ALS disrupt

nucleocytoplasmic transport; the importance of this observation is

underscored by the finding that mutations in the gene encoding GLE1,

a protein that mediates mRNA export, cause an aggressive, infantile

motor neuron disease.

Multiple studies have convincingly demonstrated that proliferating,

activated nonneuronal cells such as microglia and astrocytes importantly influence the disease course, at least in ALS-transgenic mice. A

striking additional finding in ALS and most neurodegenerative disorders is that miscreant proteins arising from gene defects in familial

forms of these diseases are often implicated in sporadic forms of the

same disorder. For example, some reports propose that nonheritable,

posttranslational modifications in SOD1 are pathogenic in sporadic

ALS; indeed, SOD1 aggregates are sometimes observed in spinal cord

in sporadic ALS without SOD1 mutations. Germline mutations in the

genes encoding β-amyloid and α-synuclein cause familial forms of Alzheimer’s and Parkinson’s diseases, and posttranslational, noninherited

abnormalities in these proteins are also central to sporadic Alzheimer’s

and Parkinson’s diseases.

TABLE 437-3 Selected Genetic Motor Neuron Diseases

DISEASE

GENE

SYMBOL GENE NAME INHERITANCE

FREQUENCY

(IN THE UNITED

STATES) USUAL ONSET

PROTEIN

FUNCTION UNUSUAL FEATURES

SPG5 CYP7B1 Cytochrome P450 AR 5–10% AR FSP Variable Degrades

endogenous

substances

Sensory loss

SPG7 SPG7 Paraplegin AR 5–10% AR FSP Variable Mitochondrial

protein

Rarely, optic atrophy,

ataxia, rarely PLS

SPG11 SPG11 Spatacsin AR 20–70% AR FSP

depends on

ethnicity

Predominantly

childhood

Cytosolic, ?

membraneassociated

Some sensory loss, thin

corpus callosum; may

mimic ALS (ALS5)

SPG39 PNPLA6 Patatin-like

phospholipase domaincontaining protein 6

/ neuropathy target

esterase

AR Early childhood Esterase May have PLS-like

phenotype

SPG44 GJC2 Gap junction protein

gamma 2/ Connexin 47

AR Childhood Gap junction

protein

Possible mild CNS

features

SPG2 PLP Proteolipid protein XR Early childhood Myelin protein Sometimes multiple CNS

features

SPG1 L1-CAM Neural cell adhesion

molecule L1 precursor

XR Infancy Cell adhesion

molecule

Adrenoleukodystrophy ABCD1 Adrenoleukodystrophy

protein

XR Early adulthood ATP binding

transporter

protein

Possible adrenal

insufficiency, CNS

inflammation

Abbreviations: AD, autosomal dominant; ALS, amyotrophic lateral sclerosis; AR, autosomal recessive; BSCL2, Bernadelli-Seip congenital lipodystrophy 2B; CNS, central

nervous system; FUS/TLS, fused in sarcoma/translocated in liposarcoma; GEF, Guanidine nucleotide exchange factor; HSP, hereditary spastic paraplegia; TDP43, Tar DNA

binding protein 43 kd; XR, X-linked recessive.

(Continued)

3415Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases CHAPTER 437

TREATMENT

Amyotrophic Lateral Sclerosis

No treatment arrests the underlying pathologic process in ALS. The

drug riluzole (100 mg/d) was approved for ALS because it produces

a modest lengthening of survival. In one trial, the survival rate at

18 months with riluzole was similar to placebo at 15 months. The

mechanism of this effect is not known with certainty; riluzole may

reduce excitotoxicity by diminishing glutamate release. Riluzole is

generally well tolerated; nausea, dizziness, weight loss, and elevated

liver enzymes occur occasionally. A second drug, edaravone, has

also been approved by the U.S. Food and Drug Administration

based on a single 6-month study in a highly selected ALS population that demonstrated a modest reduction in the trajectory of

worsening on an ALS disability scale; survival was not included as

an endpoint. This drug, which is believed to act as an antioxidant,

is administered via recurring monthly 10-day series of daily intravenous infusions. Recently the combined oral administration of

phenylbutyrate and taurursodiol was reported to slow progression

and prolong survival in ALS by improving function in mitochondria and the endoplasmic reticulum.

Interventions such as antisense oligonucleotides (ASO) and

microRNAs that diminish expression of mutant SOD1 protein prolong survival in transgenic-ALS rodent models and are also now

in clinical trials for SOD1-mediated ALS; initial pilot data from

human trials document reductions in SOD1 levels but have not yet

shown clear clinical benefit. Human trials are now also underway

for promising ASOs that suppress expression of the C9orf72 gene.

Pathophysiologic studies of mutant SOD1–related ALS in mice

have disclosed diverse targets for therapy; consequently, multiple

therapies are presently in clinical trials for ALS including experimental trials of small molecules, mesenchymal stem cells, and

immunosuppression.

In the absence of a primary therapy for ALS, a variety of rehabilitative aids may substantially assist ALS patients. Foot-drop

splints facilitate ambulation by obviating the need for excessive

hip flexion and by preventing tripping on a floppy foot. Fingerextension splints can potentiate grip. Respiratory support may be

life-sustaining. For patients electing against long-term ventilation

by tracheostomy, positive-pressure ventilation by mouth or nose

provides transient (weeks to months) relief from hypercarbia and

hypoxia. Also extremely beneficial for some patients is a respiratory

device (cough assist machine) that produces an artificial cough.

This is highly effective in clearing airways and preventing aspiration pneumonia. When bulbar disease prevents normal chewing

and swallowing, gastrostomy is uniformly helpful, restoring normal nutrition and hydration. Fortunately, an increasing variety of

speech synthesizers are now available to augment speech when

there is advanced bulbar palsy. These facilitate oral communication

and may be effective for telephone use.

In contrast to ALS, several of the disorders (Tables 437-1 and

437-3) that bear some clinical resemblance to ALS are treatable. For

this reason, a careful search for causes of secondary motor neuron

disease is warranted.

OTHER MOTOR NEURON DISEASES

■ SELECTED LOWER MOTOR NEURON DISORDERS

In these motor neuron diseases, the peripheral motor neurons are

affected without evidence of involvement of the corticospinal motor

system (Tables 437-1, 437-2, and 437-3).

X-Linked Spinobulbar Muscular Atrophy (Kennedy’s Disease)

This is an X-linked lower motor neuron disorder in which progressive

weakness and wasting of limb and bulbar muscles begins in males in

mid-adult life and is conjoined with androgen insensitivity manifested

by gynecomastia and reduced fertility (Chap. 391). In addition to

gynecomastia, which may be subtle, two findings distinguishing this

disorder from ALS are the absence of signs of pyramidal tract disease

(spasticity) and the presence of a subtle sensory neuropathy in some

patients. The underlying molecular defect is an expanded trinucleotide repeat (CAG) in the first exon of the androgen receptor gene on

the X chromosome. An inverse correlation appears to exist between the

number of CAG repeats and the age of onset of the disease.

Adult Tay-Sachs Disease Several reports have described adultonset, predominantly lower motor neuropathies arising from deficiency

of the enzyme β-hexosaminidase (hex A). These tend to be distinguishable from ALS because they are very slowly progressive and in some

cases may have been symptomatic for years; dysarthria and radiographically evident cerebellar atrophy may be prominent. In rare cases, spasticity may also be present, although it is generally absent (Chap. 419).

Spinal Muscular Atrophy The SMAs are a family of selective

lower motor neuron diseases of early onset. Despite some phenotypic

variability (largely in age of onset), the defect in the majority of families with SMA is loss of a protein (SMN, for survival motor neuron)

that is important in the formation and trafficking of RNA complexes

across the nuclear membrane. Neuropathologically these disorders are

characterized by extensive loss of large motor neurons; muscle biopsy

reveals evidence of denervation atrophy. Several clinical forms exist.

Infantile SMA (SMA I, Werdnig-Hoffmann disease) has the earliest

onset and most rapidly fatal course. In some instances, it is apparent

even before birth, as indicated by decreased fetal movements late in

the third trimester. Though alert, afflicted infants are weak and floppy

(hypotonic) and lack muscle-stretch reflexes. Death generally ensues

within the first year of life. Chronic childhood SMA (SMA II) begins later

in childhood and evolves with a more slowly progressive course. Juvenile SMA (SMA III, Kugelberg-Welander disease) manifests during late

childhood and runs a slow, indolent course. Unlike most denervating

diseases, in this chronic disorder weakness is greatest in the proximal

muscles; indeed, the pattern of clinical weakness can suggest a primary

myopathy such as limb-girdle dystrophy. Electrophysiologic and muscle

biopsy evidence of denervation distinguish SMA III from the myopathic

syndromes. Remarkably, two treatments have shown dramatic benefit

in infantile SMA. One, nusinersen, now an approved therapy, entails

administering small oligonucleotides that alter mRNA splicing of one

of the SMN genes, generating sufficient normal SMN protein to provide

clinical benefit (including prolonged survival). The other treatment uses

systemically administered adeno-associated virus (AAV) to deliver the

missing SMN gene to motor neurons and other cells.

Multifocal Motor Neuropathy with Conduction Block In this

disorder, lower motor neuron function is regionally and chronically

disrupted by focal blocks in conduction. Many cases have elevated

serum titers of mono- and polyclonal antibodies to ganglioside GM1; it

is hypothesized that the antibodies produce selective, focal, paranodal

demyelination of motor neurons. MMCB is not typically associated with

corticospinal signs. In contrast with ALS, MMCB may respond dramatically to therapy such as IV immunoglobulin or chemotherapy; thus, it is

imperative that MMCB be excluded when considering a diagnosis of ALS.

Other Forms of Lower Motor Neuron Disease In individual

families, other syndromes characterized by selective lower motor neuron dysfunction in an SMA-like pattern have been described. There

are rare X-linked and autosomal dominant forms of apparent SMA.

There is an ALS variant of juvenile onset, the Fazio-Londe syndrome,

that involves mainly the musculature innervated by the brainstem.

A component of lower motor neuron dysfunction is also found in

degenerative disorders such as Machado-Joseph disease and the related

olivopontocerebellar degenerations (Chap. 439).

■ SELECTED DISORDERS OF THE UPPER

MOTOR NEURON

Primary Lateral Sclerosis This rare disorder arises sporadically

in adults in mid-to-late life. Clinically, PLS is characterized by progressive spastic weakness of the limbs, preceded or followed by spastic

dysarthria and dysphagia, indicating combined involvement of the

3416 PART 13 Neurologic Disorders

corticospinal and corticobulbar tracts. Fasciculations, amyotrophy,

and sensory changes are absent; neither electromyography nor muscle

biopsy shows denervation. On neuropathologic examination, there is

selective loss of the large pyramidal cells in the precentral gyrus and

degeneration of the corticospinal and corticobulbar projections. The

peripheral motor neurons and other neuronal systems are spared. The

course of PLS is variable; although long-term survival is documented,

the course may be as aggressive as in ALS, with ~3-year survival from

onset to death. Early in its course, PLS raises the question of multiple

sclerosis or other demyelinating diseases as diagnostic considerations

(Chap. 444). A myelopathy suggestive of PLS is infrequently seen

with infection with the retrovirus human T-cell lymphotropic virus 1

(HTLV-1) (Chap. 442). The clinical course and laboratory testing will

distinguish these possibilities.

Hereditary Spastic Paraplegia In its pure form, HSP is usually

transmitted as an autosomal trait; most adult-onset cases are dominantly inherited. There are more than 80 genetic types of HSP for

which causative mutations in more than 60 genes have been identified.

Table 437-3 lists more commonly identified genetic types of HSP.

Symptoms usually begin in the third or fourth decade of life, presenting as progressive spastic weakness beginning in the lower extremities;

however, there are variants with onset so early that the differential

diagnosis includes cerebral palsy. HSP typically has a long survival,

presumably because respiratory function is spared. Late in the illness,

there may be urinary urgency and incontinence and sometimes fecal

incontinence; sexual function tends to be preserved.

In pure forms of HSP, the spastic leg weakness is often accompanied

by posterior column (vibration and position) abnormalities and disturbance of bowel and bladder function. Some family members may have

spasticity without clinical symptoms.

By contrast, particularly when recessively inherited, HSP may have

complex or complicated forms in which altered corticospinal and

dorsal column function is accompanied by significant involvement of

other regions of the nervous system, including amyotrophy, mental

retardation, optic atrophy, and sensory neuropathy.

Neuropathologically, in HSP there is degeneration of the corticospinal tracts, which appear nearly normal in the brainstem but show

increasing atrophy at more caudal levels in the spinal cord; in effect,

this pathologic picture is of a dying-back or distal axonopathy of long

neuronal fibers within the CNS.

Defects at numerous loci underlie both dominantly and recessively

inherited forms of HSP (Table 437-3). The gene most commonly

implicated in dominantly inherited HSP is spastin, which encodes a

microtubule interacting protein. The most common childhood-onset

dominant form arises from mutations in the atlastin gene.

An infantile-onset form of X-linked, recessive HSP arises from

mutations in the gene for myelin proteolipid protein. This is an

example of rather striking allelic variation, as most other mutations

in the same gene cause not HSP but Pelizaeus-Merzbacher disease,

a widespread disorder of CNS myelin. Another recessive variant is

caused by defects in the paraplegin gene. Paraplegin has homology to

metalloproteases that are important in mitochondrial function in yeast.

A slowly progressive, adult-onset X-linked progressive spastic paralysis designated adrenomyeloneuropathy is caused by mutations in the

ABCD1 gene; these cases are associated with elevated serum levels of

very-long-chain fatty acids (Chap. 442).

■ FURTHER READING

Brown RH, Al-Chalabi A: Review article: Amyotrophic lateral sclerosis. N Engl J Med 377:162, 2017.

Finkel RS et al: Treatment of infantile-onset spinal muscular atrophy

with nusinersin: A phase 2, open-label, dose-escalation study. Lancet

388:3017, 2016.

Gendron TF et al: Poly(GP) proteins are a useful pharmacodynamic

marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci

Transl Med 9:pii:eaai7866, 2017.

Miller TM et al: Phase 1 trial of antisense oligonucleotide tofersen for

SOD1 ALS. N Engl J Med 383:109, 2020.

Mueller C et al: SOD1 suppression with adeno-associated virus and

microRNA in familial ALS. N Engl J Med 383:151, 2020.

Robberecht W, Philips T: The changing scene of amyotrophic lateral

sclerosis. Nat Rev Neurosci 14:248, 2013.

Schüle R et al: Hereditary spastic paraplegia: Clinicogenetic lessons

from 608 patients. Ann Neurol 79:646, 2016.

Taylor JP et al: Decoding ALS: From genes to mechanism. Nature

539:197, 2016.

Van Damme P, Robberecht W: STING-Induced Inflammation—A

Novel Therapeutic Target in ALS? N Engl J Med 384:765, 2021.

Visser AE et al: Multicentre, population-based, case-control study of

particulates, combustion products and amyotrophic lateral sclerosis

risk. J Neurol Neurosurg Psychiatry 90:854, 2019.

The Writing Group on Behalf of the Edaravone (MCI-186)

ALS 19 STUDY GROUP: Safety and efficacy of edaravone in well

defined patients with amyotrophic lateral sclerosis: A randomised,

double-blind, placebo controlled trial. Lancet Neurol 16:505, 2017.

■ WEBSITES

Several websites provide valuable information on ALS including those

offered by the Muscular Dystrophy Association (www.mdausa.org),

the Amyotrophic Lateral Sclerosis Association (www.alsa.org), the

World Federation of Neurology and the Neuromuscular Unit at

Washington University in St. Louis (www.neuro.wustl.edu), and the

Northeast Amyotrophic Lateral Sclerosis Consortium (www.neals.

org).

Prions are proteins that adopt alternative conformations, which

become self-propagating. Some prions cause degeneration of the central nervous system (CNS). Once relegated to causing a group of rare

CNS disorders, such as Creutzfeldt-Jakob disease (CJD), increasing

evidence argues that prions cause more common neurodegenerative

diseases (NDs) including Alzheimer’s disease (AD) and Parkinson’s

disease (PD). While CJD is caused by the accumulation of PrPSc prions, recent investigations demonstrate unequivocally that α-synuclein

prions cause multiple system atrophy (MSA) (Chap. 440). Infectious

MSA prions have been recovered from human brain samples stored in

formalin for up to 20 years. Similar resistance to formalin was demonstrated for brain samples from sheep with scrapie. Increasingly, studies

show that Aβ and tau prions together cause AD, α-synuclein prions

cause both PD and MSA, and tau prions alone cause frontotemporal

lobar degeneration (FTLD). In this chapter, we confine our discussion

to CJD, which typically presents with a rapidly progressive dementia as

well as motor and behavioral abnormalities. The illness is relentlessly

progressive and generally causes death within 7 months of onset. Most

patients with CJD are between 50 and 75 years of age; however, patients

as young as 12 and as old as 96 have been recorded. The role of prions

in the pathogenesis of NDs is reviewed in Chap. 424.

CJD is one malady in a group of disorders caused by prions composed of the prion protein (PrP). PrP prions reproduce by binding to

the normal, cellular isoform of the prion protein (PrPC) and stimulating conversion of PrPC into the disease-causing isoform PrPSc. PrPC is

rich in α-helix and has little β-structure, whereas PrPSc has less α-helix

and a high amount of β-structure. The α-to-β structural transition in

PrP is the fundamental event underlying this group of prion diseases

(Table 438-1).

Four new concepts have emerged from studies of PrP prions: (1)

Prions are the only known transmissible pathogens that are devoid of

nucleic acid; all other infectious agents possess genomes composed of

438 Prion Diseases

Stanley B. Prusiner, Michael Geschwind

3417Prion Diseases CHAPTER 438

cannibalism. Whether BSE began as a sporadic case of BSE in a cow or

started with scrapie in sheep is unknown. The origin of chronic wasting

disease (CWD), a prion disease endemic in deer and elk in regions of

North America, and more recently identified in isolated populations

in Scandinavia and Korea, is uncertain. In contrast to other prion diseases, CWD is highly communicable among cervids. Bodily excretions,

such as feces, urine, and saliva, from asymptomatic, infected cervids

contain prions that are likely to be responsible for the spread of CWD.

■ EPIDEMIOLOGY

CJD is found throughout the world. The incidence of sCJD is ~1 case

per million population, although a person’s lifetime risk of dying from

CJD is ~1 in 5000 deaths. Because sCJD is an age-dependent ND, its

incidence is expected to increase steadily as older segments of populations in developed and developing countries continue to expand.

Although many geographic clusters of CJD have been reported, each

has been shown to segregate with a PrP gene mutation and/or included

misdiagnoses. Attempts to identify common exposure to some etiologic agent have been unsuccessful for both the sporadic and familial

cases. Ingestion of scrapie-infected sheep or goats as a cause of CJD in

humans has not been demonstrated by epidemiologic studies, although

speculation about this potential route of infection continues. Of particular interest are deer hunters who develop CJD, because up to 90%

of culled deer in some game herds have been shown to harbor CWD

prions. Whether PrP prion disease in deer, elk, or moose has passed

to cows, sheep, or directly to humans remains unknown. Studies with

rodents demonstrate that oral infection with prions can occur, but the

process is inefficient compared to intracerebral inoculation.

■ PATHOGENESIS

The human PrP prion diseases were initially classified as NDs of

unknown etiology on the basis of pathologic changes being confined to

the CNS. Even though the familial nature of GSS and a subset of CJD

TABLE 438-1 Glossary of PrP Prion Terminology

Prion Proteinaceous infectious particle that lacks nucleic acid.

Prions are composed entirely of alternatively folded proteins

that undergo self-propagation. Distinct strains of prions exhibit

different biologic properties, which are epigenetically heritable.

PrP prions cause scrapie in sheep and goats, mad cow disease,

and related neurodegenerative diseases of humans such as

Creutzfeldt-Jakob disease (CJD).

PrPSc Disease-causing Scrapie isoform of the prion protein. This

protein is the only identifiable macromolecule in purified

preparations of scrapie prions.

PrPC Cellular isoform of the prion protein. PrPC

 is the precursor

of PrPSc.

PrP 27-30 A fragment of PrPSc, generated by truncation of the NH2

-

terminus by limited digestion with proteinase K. PrP 27-30

retains prion infectivity and polymerizes into amyloid.

PRNP PrP gene located on human chromosome 20.

Prion rod An aggregate of prions composed largely of PrP 27-30

molecules. Created by detergent extraction and limited

proteolysis of PrPSc. Morphologically and histochemically

indistinguishable from many amyloids.

PrP amyloid Amyloid containing PrP in the brains of animals or humans with

prion disease; often accumulates as plaques.

TABLE 438-2 The PrP Prion Diseases

DISEASE HOST MECHANISM OF PATHOGENESIS

Human

Kuru Fore people Infection through ritualistic

cannibalism

iCJD Humans Infection from prion-contaminated

hGH, dura mater grafts, etc.

vCJD Humans Infection from bovine prions

fCJD Humans Germline mutations in PRNP

GSS Humans Germline mutations in PRNP

FFI Humans Germline mutation in PRNP (D178N,

M129)

sCJD Humans Somatic mutation or spontaneous

conversion of PrPC

 into PrPSc?

sFI Humans Somatic mutation or spontaneous

conversion of PrPC

 into PrPSc?

Animal

Scrapie Sheep, goats Infection in genetically susceptible

sheep and goats

BSE Cattle Infection with prion-contaminated

MBM

TME Mink Infection with prions from sheep or

cattle

CWD Mule deer, elk Unknown

FSE Cats Infection with prion-contaminated beef

Exotic ungulate

encephalopathy

Greater kudu,

nyala, or oryx

Infection with prion-contaminated

MBM

Abbreviations: BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob

disease; CWD, chronic wasting disease; fCJD, familial Creutzfeldt-Jakob disease;

FFI, fatal familial insomnia; FSE, feline spongiform encephalopathy; GSS,

Gerstmann-Sträussler-Scheinker disease; hGH, human growth hormone; iCJD,

iatrogenic Creutzfeldt-Jakob disease; MBM, meat and bone meal; sCJD, sporadic

Creutzfeldt-Jakob disease; sFI, sporadic fatal insomnia; TME, transmissible mink

encephalopathy; vCJD, variant Creutzfeldt-Jakob disease.

either RNA or DNA that direct the synthesis of their progeny. (2) Prion

diseases may manifest as infectious, genetic, or sporadic disorders; no

other group of illnesses with a single etiology presents with such a wide

spectrum of clinical manifestations. (3) Prion diseases result from the

accumulation of PrPSc, the conformation of which differs substantially

from that of its precursor, PrPC. (4) Distinct strains of prions exhibit

different biologic properties, which are epigenetically inherited. In

other words, PrPSc can exist in a variety of different conformations,

many of which seem to specify particular disease phenotypes.

How a specific conformation of a PrPSc molecule is imparted to

PrPC during prion replication to produce nascent PrPSc with the same

conformation is not well understood. Additionally, it is unclear what

factors determine where in the CNS a particular PrPSc molecule will

be created.

SPECTRUM OF PrP PRION DISEASES

The sporadic form of CJD is the most common PrP prion disorder in

humans. Sporadic CJD (sCJD) accounts for ~85% of all cases of human

PrP prion disease, and genetic prion diseases account for 10–15% of all

cases (Table 438-2). Genetic prion diseases were historically divided

into three forms: familial CJD (fCJD), Gerstmann-Sträussler-Scheinker

(GSS) disease, and fatal familial insomnia (FFI). All dominantly inherited PrP prion diseases are caused by mutations in the PrP gene.

Although infectious PrP prion diseases account for <1% of all cases

and infection does not seem to play an important role in the natural

history of these illnesses, the transmissibility of PrP prions is an important biologic feature. Kuru of the Fore people of Papua New Guinea is

well established to have resulted from the consumption of brains from

dead relatives during ritualistic cannibalism. After the cessation of

ritualistic cannibalism in the late 1950s, kuru nearly disappeared, with

the exception of a few recent patients exhibiting incubation periods of

>40 years. Iatrogenic CJD (iCJD) seems to be the result of the accidental inoculation of patients with prions. Variant CJD (vCJD) in

teenagers and young adults in Europe is the result of exposure to

tainted beef from cattle with bovine spongiform encephalopathy (BSE).

Although occasional cases of iCJD still occur, this form of CJD is currently on the decline due to public health measures aimed at preventing

the spread of PrP prions.

More than seven diseases of animals are caused by prions

(Table 438-2). Scrapie of sheep and goats is the prototypic PrP prion

disease. Mink encephalopathy, BSE, feline spongiform encephalopathy,

and exotic ungulate encephalopathy are all thought to occur after the

consumption of prion-infected foodstuffs. The BSE epidemic emerged

in Britain in the late 1980s and was shown to be due to industrial

3418 PART 13 Neurologic Disorders

cases was well described, the significance of this observation became

more obscure with the transmission of GSS and CJD to animals. With

the transmission of kuru and CJD to nonhuman primates, investigators

began to view these diseases as infectious CNS illnesses caused by slow

viruses. Eventually, the familial nature of GSS and a minority of CJD

cases became clear with the discovery in 1989 of mutations in the PrP

gene (PRNP) of these patients. The prion concept explains how a single

disease can manifest as sporadic, heritable, and infectious. Moreover,

the hallmark of all PrP prion diseases, whether sporadic, dominantly

inherited, or acquired by infection, is that they involve the aberrant

folding of the PrP protein.

A major feature that distinguishes PrP prions from viruses is the

finding that both PrP isoforms are encoded by a chromosomal gene. In

humans, the PrP gene is designated PRNP and is located on the short

arm of chromosome 20. Limited proteolysis of PrPSc produces a smaller,

protease-resistant molecule of ~142 amino acids designated PrP 27-30;

PrPC is completely hydrolyzed under the same conditions (Fig. 438-1).

PrP 27-30 polymerizes into prion rods that are morphologically indistinguishable from the filaments that aggregate to form PrP amyloid

plaques in the CNS. This discovery raised the possibility that many

other NDs might be caused by different proteins, all of which can fold

into prions.

Prion Strains Distinct strains of PrP prions exhibit different biologic properties, which are epigenetically heritable. The existence of

prion strains raised the question of how heritable biologic information

can be enciphered in a molecule other than nucleic acid. Various

strains of PrP prions have been defined by incubation times, distribution of neuronal vacuolation on neuropathology, and stabilities of PrPSc

to denaturation. Subsequently, the patterns of PrPSc deposition were

found to correlate with vacuolation profiles, and these patterns were

also used to characterize prion strains.

Persuasive evidence that strain-specific information is enciphered in

the tertiary structure of PrPSc comes from transmission of two different

inherited human prion diseases to mice expressing a chimeric human–

mouse PrP transgene. In most forms of fCJD and the majority of sCJD

cases, the protease-resistant fragment of PrPSc after deglycosylation has

a molecular mass of 21 kDa (i.e., type 1 prions), whereas in FFI, and

a minority of sCJD cases, it is 19 kDa (type 2 prions) (Table 438-3).

This difference in molecular mass was shown to be due to different

sites of proteolytic cleavage at the NH2

 termini of the two human PrPSc

molecules, reflecting different tertiary structures. These distinct conformations were not unexpected because the amino acid sequences of

the PrP fragments differ. Extracts from the brains of patients with FFI

transmitted disease to the mice expressing the chimeric human–mouse

PrP transgene and resulted in the formation of 19-kDa PrPSc, whereas

brain extracts from fCJD and sCJD patients harboring 21-kDa PrPSc

resulted in 21-kDa PrPSc in mice expressing the same transgene. On

second passage, these differences were maintained, demonstrating that

chimeric PrPSc can exist in two different conformations as demonstrated by the sizes of the protease-resistant fragments, even though the

amino acid sequence of PrPSc is invariant.

This analysis was extended when patients with sporadic fatal insomnia (sFI) were identified. Although they did not carry a PRNP mutation, the patients demonstrated a clinical and pathologic phenotype

that was indistinguishable from that of patients with FFI. Furthermore,

19-kDa PrPSc was found in their brains, and on passage of sFI prion

disease to mice expressing the chimeric human–mouse PrP transgene,

19-kDa PrPSc was also found. These findings indicate that the disease

phenotype is dictated by the conformation of PrPSc and not the amino

acid sequence. PrPSc acts as a template for the conversion of PrPC into

nascent PrPSc. On the passage of prions into mice expressing a chimeric

hamster–mouse PrP transgene, a change in the conformation of PrPSc

was accompanied by the emergence of a new strain of prions.

Many new strains of prions were generated using recombinant (rec)

PrP produced in bacteria; recPrP was polymerized into amyloid fibrils

to make “synthetic prions,” which were inoculated into transgenic mice

over-expressing high levels of wild-type mouse PrPC. Approximately

500 days later, the mice died of prion disease. The incubation times of

the “synthetic prions” in mice were dependent on the conditions used

for polymerization of the amyloid fibrils, which affected the stability of

those amyloid fibrils. Highly stable amyloids gave rise to stable prions

with long incubation times; low-stability amyloids led to prions with

short incubation times. Amyloids of intermediate stability gave rise to

prions with intermediate stabilities and intermediate incubation times.

Such findings are consistent with earlier studies showing that the incubation times of synthetic and naturally occurring prions are directly

proportional to the stability of the prion.

Species Barrier Studies on the role of the primary and tertiary

structures of PrP in the transmission of prion disease have provided

new insights into the pathogenesis of these maladies. The amino acid

sequence of PrP encodes the species of the prion, and the prion derives

its PrPSc sequence from the last mammal in which it was passaged.

While the primary structure of PrP is likely to be the most important

or even the sole determinant of the tertiary structure of PrPC, PrPSc

seems to function as a template in determining the tertiary structure of

nascent PrPSc molecules as they are formed from PrPC. In turn, prion

TABLE 438-3 Distinct Prion Strains Generated in Humans with Inherited Prion Diseases and Transmitted to Transgenic Micea

INOCULUM HOST SPECIES HOST PrP GENOTYPE INCUBATION TIME [DAYS ± SEM] (n/n0

) PrPSc

 (kDa)

None Human FFI(D178N, M129) 19

FFI Mouse Tg(MHu2M) 206 ± 7 (7/7) 19

FFI → Tg(MHu2M) Mouse Tg(MHu2M) 136 ± 1 (6/6) 19

None Human fCJD(E200K) 21

fCJD Mouse Tg(MHu2M) 170 ± 2 (10/10) 21

fCJD → Tg(MHu2M) Mouse Tg(MHu2M) 167 ± 3 (15/15) 21

a

Tg(MHu2M) mice express a chimeric mouse-human PrP gene.

Notes: Clinicopathologic phenotype is determined by the conformation of PrPSc in accord with the results of the transmission of human prions from patients with FFI to

transgenic mice.

Abbreviations: fCJD, familial Creutzfeldt-Jakob disease; FFI, fatal familial insomnia; SEM, standard error of the mean.

PrP Polypeptide

PrPC

PrPSc

CHO CHO GPI

S S

PrP 27-30

Codon

209 amino acids

209 amino acids

~142 amino acids

1 23 50 94 131 188 231 254

FIGURE 438-1 PrP prion protein isoforms. Bar diagram of Syrian hamster PrP, which

consists of 254 amino acids. After processing of the NH2

 and COOH termini, both PrPC

and PrPSc consist of 209 residues. After limited proteolysis, the NH2

 terminus of PrPSc

is truncated to form PrP 27-30 composed of ~142 amino acids. CHO, N-linked sugars;

GPI, glycosylphosphatidylinositol anchor attachment site; S–S, disulfide bond.

3419Prion Diseases CHAPTER 438

diversity appears to be enciphered in the conformation of PrPSc, and

thus prion strains seem to represent different conformers of PrPSc.

In general, transmission of PrP prion disease from one species to

another is inefficient, in that not all intracerebrally inoculated animals

develop disease, and those that fall ill do so only after long incubation

times that can approach the natural life span of the animal. This “species barrier” to transmission is correlated with the degree of similarity

between the amino acid sequences of PrPC in the inoculated host and of

PrPSc in the inoculum. The importance of sequence similarity between

the host and donor PrP argues that PrPC directly interacts with PrPSc in

the prion conversion process.

SPORADIC AND INHERITED

PrP PRION DISEASES

Several different scenarios might explain the initiation of sporadic

prion disease: (1) A somatic mutation may be the cause and thus follow

a path similar to that for germline mutations in inherited disease. In

this situation, the mutant PrPSc must be capable of targeting wild-type

PrPC, a process known to be possible for some mutations but less likely

for others. (2) The activation energy barrier separating wild-type PrPC

from PrPSc could be crossed on rare occasions when viewed in the

context of a population. Most individuals would be spared, but presentations in older persons, with an incidence of ~1 per million, would be

seen. (3) PrPSc may be present at low levels in some normal cells, where

it performs an important, but as yet unknown, function. The level of

PrPSc in such cells is hypothesized to be sufficiently low as not to be

detected by routine bioassay. In some altered metabolic states, the cellular mechanisms for clearing PrPSc might become compromised, and

the rate of PrPSc formation would then begin to exceed the capacity of

the cell to clear it. The third possible mechanism is attractive because

it suggests that PrPSc is not simply a misfolded protein, as proposed for

the first and second mechanisms, but that it is an alternatively folded

molecule with a function. Moreover, the multitude of conformational

states that PrPSc can adopt, as described above, raises the possibility

that PrPSc or another protein might function in a process such as shortterm memory where information storage is thought to occur in the

absence of new protein synthesis.

More than 40 different mutations resulting in nonconservative substitutions in the human PRNP gene have been found to segregate with

inherited human prion diseases. Missense mutations, a deletion, and

expansions in the octapeptide repeat region of the gene, called octapeptide repeat insertions (OPRIs), are responsible for genetic forms of

prion disease.

Although phenotypes may vary dramatically, even within families,

specific phenotypes observed with certain mutations appear to cause

sCJD. More than 20 missense variants—including substitutions at

codons 102, 105, 117, 198, and 217, and mid to longer OPRIs—cause

the GSS form of PrP prion disease with prominent parkinsonian and

cerebellar features. Regarding OPRI mutations, the normal human PrP

sequence contains an unstable section in the N-terminal region comprised of five repeats—a nine-amino-acid sequence or nonapeptide

(R1) followed by four octapeptide repeats. Insertions from 2 to 12 extra

octapeptide repeats frequently cause variable phenotypes including

conditions indistinguishable from sCJD, GSS-like presentations, and

even a slowly progressive dementing illness of many years in duration

to an early-age-of-onset disorder that is similar to AD. A mutation at

codon 178 that results in substitution of asparagine for aspartic acid

generally causes FFI if methionine is encoded at codon 129 on the same

allele. In contrast, a typical dementing CJD phenotype has been generally found with a valine encoded at codon 129 of the same allele. Stop

codon (nonsense) mutations are rare and cause a range of phenotypes,

including some with a prolonged course of years to decades, GSS- or

AD-like presentations, autonomic and sensory peripheral nervous

system involvement, chronic gastrointestinal upset, and extensive PrPSc

amyloid deposits.

■ HUMAN PRNP GENE POLYMORPHISMS

Polymorphisms influence the susceptibility to sporadic, genetic,

and acquired forms of PrP prion disease. The methionine/valine

polymorphism at codon 129 of PRNP not only modulates the age of

onset of some genetic prion diseases but also can affect the clinical

phenotype. The findings that homozygosity at codon 129 (both alleles

being either methionine [M] or valine [V]) predisposes an individual

to sCJD and that codon 129 MM predisposes a person to vCJD support a model of prion production that favors PrP interactions between

homologous proteins.

Substitution of the basic residue lysine at position 218 in mouse

PrP produced dominant-negative inhibition of prion replication in

transgenic mice. This same lysine at position 219 in human PrP has

been found in 12% of the Japanese population, a group that appears

to be resistant to prion disease. Dominant-negative inhibition of prion

replication was also found with substitution of the basic residue arginine

at position 171; sheep with arginine were resistant to scrapie prions but

were susceptible to BSE prions that were inoculated intracerebrally. A

very interesting polymorphism at codon 127 in PRNP was identified

among longtime survivors of the kuru epidemic in the Fore ethnic group

of Papua New Guinea, which when expressed in transgenic mice with

humanized PRNP prevented the animals from acquiring prion disease.

ACQUIRED PrP PRION DISEASES

■ IATROGENIC CJD

Accidental transmission of CJD to humans appears to have occurred

with corneal transplantation, contaminated electroencephalogram

(EEG) electrode implantation, and surgical procedures. Corneas from

donors with unsuspected CJD have been transplanted to apparently

healthy recipients who developed CJD after variable incubation periods. The same improperly decontaminated EEG electrodes that caused

CJD in two young patients with intractable epilepsy caused CJD in a

chimpanzee 18 months after their experimental implantation.

Surgical procedures may have resulted in accidental inoculation of

patients with prions, presumably because some instrument or apparatus in the operating theater became contaminated when a CJD patient

underwent surgery. Although the epidemiology of these studies is

highly suggestive, no proof for such episodes exists.

Dura Mater Grafts More than 160 cases of CJD after implantation of dura mater grafts have been recorded. All of the grafts appear

to have been acquired from a single manufacturer whose preparative

procedures were inadequate to inactivate human prions. One case of

CJD occurred after repair of an eardrum perforation with a pericardium graft.

Human Growth Hormone and Pituitary Gonadotropin Therapy

The transmission of CJD prions from contaminated human growth

hormone (hGH) preparations derived from human pituitaries has

been responsible for fatal cerebellar disorders with dementia in

>180 patients ranging in age from 10 to 41 years. These patients

received injections of hGH every 2–4 days for 4–12 years. If it is

thought that these patients developed CJD from injections of prioncontaminated hGH preparations, the possible incubation periods range

from 4 to 30 years. Only recombinant hGH is now used therapeutically

so that possible contamination with prions is no longer an issue.

Notably, evidence has accumulated in deceased patients with hGH

CJD that some also carry Aβ prions. This finding demonstrated the

iatrogenic propagation of Aβ prions in the human CNS.

Four cases of CJD have occurred in women receiving human pituitary gonadotropin.

■ VARIANT CJD

The restricted geographic occurrence and chronology of vCJD raised

the possibility that BSE prions had been transmitted to humans

through the consumption of tainted beef. More than 190 cases of vCJD

have occurred, with >90% of these in Britain. Variant CJD has also

been reported in people either living in or originating from France,

Ireland, Italy, the Netherlands, Portugal, Spain, Saudi Arabia, the

United States, Canada, and Japan.

The steady decline in the number of vCJD cases over the past

decade argues either that there will not be a prion disease epidemic in

3420 PART 13 Neurologic Disorders

Europe, similar to those seen for BSE and kuru. What is certain is that

PrP-prion-tainted meat should be prevented from entering the human

food supply.

The most compelling evidence that vCJD is caused by BSE prions

was obtained from experiments in mice expressing the bovine PrP

transgene. Both BSE and vCJD prions were efficiently transmitted to

these transgenic mice and with similar incubation periods. In contrast

to sCJD prions, vCJD prions did not transmit disease efficiently to

mice expressing a chimeric human–mouse PrP transgene. Earlier studies with nontransgenic mice suggested that vCJD and BSE might be

derived from the same source because both inocula transmitted disease

with similar but very long incubation periods.

Attempts to determine the origin of BSE and vCJD prions have

relied on passaging studies in mice, some of which are described

above, as well as studies of the conformation and glycosylation of

PrPSc. One scenario suggests that a particular conformation of bovine

PrPSc was selected for heat resistance during the rendering process

and was then reselected multiple times as cattle infected by ingesting

prion-contaminated meat and bone meal (MBM) were slaughtered and

their offal rendered into more MBM. Variant CJD cases have virtually

disappeared with protection of the beef supply in Europe. Interestingly,

almost all of the approximately 238 cases of vCJD reported as of 2021

have been homozygous for methionine (MM) at codon 129 in PRNP,

except two of the more recent cases were codon 129 MV, which is the

most common codon 129 polymorphism.

■ NEUROPATHOLOGY

Frequently, the brains of patients with CJD have no recognizable

abnormalities on gross examination. Patients who survive for several

years have variable degrees of cerebral atrophy.

On light microscopy, the pathologic hallmarks of CJD are spongiform degeneration (vacuolation), neuronal loss, and astrocytic gliosis.

The lack of an inflammatory response in CJD and other prion diseases

is an important pathologic feature of these degenerative disorders.

Spongiform degeneration is characterized by many 1- to 5-μm vacuoles in the neuropil between nerve cell bodies. Generally, the spongiform changes occur in the cerebral cortex, putamen, caudate nucleus,

thalamus, and molecular layer of the cerebellum. Astrocytic gliosis is

a constant but nonspecific feature of PrP prion diseases. Widespread

proliferation of fibrous astrocytes is found throughout the gray matter

of brains infected with CJD prions. Astrocytic processes filled with glial

filaments form extensive networks.

Amyloid plaques have been found in ~10% of CJD cases. Purified

CJD prions from humans and animals exhibit the ultrastructural and

histochemical characteristics of amyloid when treated with detergents

during limited proteolysis. On first passage of samples from some

human Japanese CJD cases into mice, amyloid plaques were found.

These plaques stain with antibodies raised against PrP, demonstrating

that the amyloid is composed of PrP.

The amyloid plaques of GSS disease are morphologically distinct

from those seen in kuru or scrapie. GSS plaques consist of a central

dense core of amyloid surrounded by smaller globules of amyloid.

Ultrastructurally, they consist of a radiating fibrillar network of amyloid fibrils, with scant or no neuritic degeneration. The plaques can be

distributed throughout the brain but are most frequently found in the

cerebellum. They are often located adjacent to blood vessels. Congophilic angiopathy has been noted in some cases of GSS disease.

In vCJD, a characteristic feature is the presence of “florid plaques.”

These are composed of a central core of PrP amyloid, surrounded by

vacuoles in a pattern suggesting petals on a flower.

■ CLINICAL FEATURES

Nonspecific prodromal symptoms occur in approximately a third of

patients with CJD and may include fatigue, sleep disturbance, weight

loss, headache, anxiety, vertigo, malaise, and ill-defined pain. Most

patients with CJD present with deficits in higher cortical function.

Behavioral and psychiatric symptoms, such as depression, apathy,

insomnia, appetite changes, psychosis, and visual hallucinations, are

very common and often the defining features of the illness. These

deficits almost always progress over weeks or months to a state of

profound dementia characterized by memory loss, impaired judgment,

and a decline in virtually all aspects of intellectual function. A few

patients present early with either isolated visual impairment or cerebellar gait and coordination deficits, referred to as the Heidenhain and

Brownell-Oppenheim variants, respectively. Frequently, the cerebellar

deficits are rapidly followed by progressive dementia. Visual problems

often begin with blurred vision and diminished acuity, rapidly followed

by dementia. Patients with early visual deficits appear to have a faster

decline overall.

Other symptoms and signs include extrapyramidal dysfunction

manifested as rigidity, masklike facies, dystonia, myoclonus, or less

commonly choreoathetoid movements and pyramidal signs (usually

mild and not actual weakness). Some uncommon features include

seizures (usually major motor), hypoesthesia, supranuclear gaze

palsy, motor neuron disease, optic atrophy, and vegetative signs such

as changes in weight, temperature, sweating, or menstruation.

Myoclonus A majority of patients with CJD eventually develop

myoclonus that appears at various times throughout the illness. Unlike

other involuntary movements, myoclonus persists during sleep. Startle

myoclonus elicited by loud sounds or bright lights is frequent. It is

important to stress that myoclonus is neither specific nor confined

to CJD and tends to occur later in the course of CJD. Dementia with

myoclonus can also be due to AD (Chap. 431), dementia with Lewy

bodies (Chap. 434), corticobasal degeneration (Chap. 432), cryptococcal encephalitis (Chap. 215), or the myoclonic epilepsy disorder

Unverricht-Lundborg disease (Chap. 425).

Clinical Course In documented cases of accidental transmission

of CJD to humans, an incubation period of 1.5–2 years preceded the

development of clinical disease. In other cases, incubation periods

>40 years have been suggested. Most patients with CJD live 6–12 months

after the onset of clinical signs and symptoms, whereas some live for up

to a few years. Some mutations causing genetic prion disease can have

durations of a decade or longer.

■ DIAGNOSIS

The constellation of dementia, myoclonus, and periodic electrical

bursts in an afebrile 60-year-old patient generally indicates CJD. Clinical abnormalities in CJD are confined to the CNS. Fever, elevated sedimentation rate, leukocytosis in blood, or a pleocytosis in cerebrospinal

fluid (CSF) should alert the physician to another etiology to explain

the patient’s CNS dysfunction, although there are rare cases of CJD in

which mild CSF pleocytosis is observed.

Variations in the typical course appear in inherited and transmitted

forms of the disease. Most mutations causing fCJD have a slightly

earlier mean age of onset, although usually an otherwise similar clinical and radiologic presentation to sCJD. In GSS, ataxia is usually a

prominent and presenting feature, with dementia occurring late in the

disease course. GSS presents earlier than sCJD (mean age 43 years) and

is typically more slowly progressive than sCJD; death usually occurs

within 5 years of onset. FFI is characterized by insomnia and dysautonomia; dementia occurs only in the terminal phase of the illness.

Rare sporadic cases have been identified. Variant CJD has an unusual

clinical course, with a prominent psychiatric prodrome that may

include visual hallucinations and early ataxia, whereas frank dementia

is usually a late sign of vCJD.

■ DIFFERENTIAL DIAGNOSIS

Many conditions mimic CJD. Dementia with Lewy bodies (Chap. 434)

is the most common disorder to be mistaken for CJD. It can present

in a subacute fashion with delirium, myoclonus, and extrapyramidal

features. Other neurodegenerative disorders to consider include AD,

FTD, corticobasal degeneration, progressive supranuclear palsy, ceroid

lipofuscinosis, and myoclonic epilepsy with Lafora bodies. The absence

of abnormalities on diffusion-weighted and fluid-attenuated inversion

3421Prion Diseases CHAPTER 438

recovery (FLAIR) MRI will almost always distinguish these dementing

conditions from CJD.

Hashimoto’s encephalopathy, which presents as a subacute progressive encephalopathy with myoclonus and periodic triphasic complexes

on the EEG, should be excluded in every case of suspected CJD. It

is diagnosed by the finding of high titers of antithyroglobulin or

antithyroid peroxidase (antimicrosomal) antibodies in the blood and

improves with glucocorticoid therapy. Unlike CJD, fluctuations in

severity typically occur in Hashimoto’s encephalopathy.

Intracranial vasculitides (Chap. 363) may produce nearly all of the

symptoms and signs associated with CJD, sometimes without systemic

abnormalities. Myoclonus is exceptional with cerebral vasculitis, but

focal seizures may confuse the picture. Prominent headache, absence

of myoclonus, stepwise change in deficits, abnormal CSF, and focal

white matter change on MRI or angiographic abnormalities all favor

vasculitis.

Autoimmune and paraneoplastic conditions (Chap. 94), particularly

limbic encephalitis and cortical encephalitis, can also mimic CJD. In many

of these patients, dementia appears prior to the diagnosis of a tumor, and

in some, no tumor is ever found. Detection of the paraneoplastic antibodies is often the only way to distinguish these cases from CJD.

Other diseases that can simulate CJD include neurosyphilis

(Chap. 182), AIDS dementia complex (Chap. 202), progressive multifocal leukoencephalopathy (Chap. 137), subacute sclerosing panencephalitis, progressive rubella panencephalitis, herpes simplex encephalitis

(Chap. 137), diffuse intracranial tumor (gliomatosis cerebri; Chap. 90),

anoxic encephalopathy, dialysis dementia, uremia, hepatic encephalopathy, and lithium or bismuth intoxication.

■ LABORATORY TESTS

The only specific diagnostic tests for CJD and other human PrP prion

diseases measure PrPSc. The most widely used method involves limited

proteolysis that generates PrP 27-30, which is detected by immunoassay after denaturation. The conformation-dependent immunoassay

(CDI) is based on immunoreactive epitopes that are exposed in PrPC

but buried in PrPSc. In humans, the diagnosis of CJD can be established

by brain biopsy if PrPSc is detected although biopsy is rarely indicated.

If no attempt is made to measure PrPSc, but the constellation of pathologic changes frequently found in CJD is seen in a brain biopsy, then

the diagnosis is reasonably secure (see “Neuropathology,” above).

The high sensitivity and specificity of cortical ribboning and basal

ganglia hyperintensity on FLAIR and diffusion-weighted MRI for the

diagnosis of CJD have greatly diminished the need for brain biopsy in

patients with suspected CJD. Because PrPSc is not uniformly distributed

throughout the CNS, the apparent absence of PrPSc in a limited sample

such as a biopsy does not rule out prion disease. At autopsy, sufficient

brain samples should be taken for both PrPSc immunoassay, preferably

by CDI, and immunohistochemistry of tissue sections.

To establish the diagnosis of either sCJD or familial prion disease,

sequencing the PRNP gene must be performed. Finding the wild-type

PRNP gene sequence permits the diagnosis of sCJD if there is no

history to suggest infection from an exogenous source of prions. The

identification of a mutation in the PRNP gene sequence that encodes

a nonconservative amino acid substitution argues for familial prion

disease.

MRI is valuable for distinguishing sCJD from most other conditions. On FLAIR sequences and diffusion-weighted imaging, ~90% of

patients show increased intensity in the basal ganglia and cortical ribboning (Fig. 438-2). This pattern is not seen with other neurodegenerative disorders but has been seen infrequently with viral encephalitis,

paraneoplastic syndromes, or seizures. When the typical MRI pattern

is present, in the proper clinical setting, diagnosis is facilitated. However, some cases of sCJD do not show this typical pattern, and other

early diagnostic approaches are still needed. CT findings are generally

nonspecific; they may be normal or show cortical atrophy.

CSF is nearly always normal but may show protein elevation and,

rarely, mild pleocytosis. Although the stress protein 14-3-3 is elevated

in the CSF of some patients with CJD, similar elevations of 14-3-3 are

found in patients with other disorders; thus, this elevation is not specific. Similarly, elevations of CSF neuron-specific enolase and tau occur

in CJD but lack specificity for diagnosis.

The EEG is often useful in the diagnosis of CJD, although only ~60%

of individuals show the typical pattern, which appears quite late in

the clinical course. During the early phase of CJD, the EEG is usually

normal or shows only scattered theta activity. In most advanced cases,

repetitive, high-voltage, triphasic, and polyphasic sharp discharges are

seen, but in many cases, their presence is transient. The presence of

these stereotyped periodic bursts of <200 ms in duration, occurring

every 1–2 s, makes the diagnosis of CJD very likely. These discharges

are frequently but not always symmetric; there may be a one-sided

predominance in amplitude. As CJD progresses, normal background

rhythms become fragmentary and slower.

■ CARE OF CJD PATIENTS

Although CJD is communicable, the likelihood of transmission from

one patient to another is remote. The risk of accidental inoculation

by aerosols is small; nonetheless, procedures producing aerosols

should be performed in certified biosafety cabinets. Biosafety level 2

practices, containment equipment, and facilities are recommended

by the Centers for Disease Control and Prevention and the National

Institutes of Health. The primary worry in caring for patients with

CJD is the inadvertent infection of health care workers by needle and

stab wounds, although with the possible exception of vCJD even blood

transfusions appear to carry minimal risk for transmission. Electroencephalographic and electromyographic needles should not be reused

after studies on patients with CJD have been performed.

Autopsies on patients whose clinical diagnosis is CJD can be performed with minimal risk to pathologists or other morgue employees.

Standard microbiologic practices outlined here, along with specific

recommendations for decontamination, are generally adequate precautions for the care of patients with CJD and the handling of infected

specimens.

■ DECONTAMINATION OF CJD PRIONS

Prions are generally resistant to commonly used inactivation procedures, and there is some disagreement about the optimal conditions

for sterilization. Some investigators recommend treating CJDcontaminated materials once with 1 N NaOH at room temperature,

FIGURE 438-2 T2-weighted FLAIR MRI showing hyperintensity in the cortex in a

patient with sCJD. This so-called cortical ribboning along with increased intensity

in the basal ganglia on T2- or diffusion-weighted imaging can aid in the diagnosis

of CJD.

3422 PART 13 Neurologic Disorders

APPROACH TO THE PATIENT

Ataxic Disorders

Symptoms and signs of ataxia consist of gait impairment, unclear

(“scanning”) speech, visual blurring due to nystagmus, hand incoordination, and tremor with movement. These result from the

involvement of the cerebellum and its afferent and efferent pathways, including the spinocerebellar pathways, and the frontopontocerebellar pathway originating in the rostral frontal lobe. True

cerebellar ataxia must be distinguished from ataxia associated with

vestibular nerve or labyrinthine disease, as the latter results in a

disorder of gait associated with a significant degree of dizziness,

light-headedness, or the perception of movement (Chap. 19). True

cerebellar ataxia is devoid of these vertiginous complaints and is

clearly an unsteady gait due to imbalance. Sensory disturbances can

also on occasion simulate the imbalance of cerebellar disease; with

sensory ataxia, imbalance dramatically worsens when visual input is

removed (Romberg sign). Rarely, weakness of proximal leg muscles

mimics cerebellar disease. In the patient who presents with ataxia,

the rate and pattern of the development of cerebellar symptoms

help to narrow the diagnostic possibilities (Table 439-1). A gradual

and progressive increase in symptoms with bilateral and symmetric

involvement suggests a genetic, metabolic, immune, or toxic etiology. Conversely, focal, unilateral symptoms with headache and

impaired level of consciousness accompanied by ipsilateral cranial

nerve palsies and contralateral weakness imply a space-occupying

cerebellar lesion.

439 Ataxic Disorders

Roger N. Rosenberg

but we believe this procedure may be inadequate for sterilization.

Autoclaving at 134°C for 5 h or treatment with 2 N NaOH for several

hours is recommended for sterilization of prions. The term sterilization

implies complete destruction of prions; any residual infectivity can be

hazardous. Transgenic mouse studies show that sCJD prions bound to

stainless-steel surfaces are resistant to inactivation by autoclaving at

134°C for 2 h; exposure of bound prions to an acidic detergent solution

prior to autoclaving rendered prions susceptible to inactivation. Recent

studies show that α-synuclein prions in brain homogenates prepared

from MSA patients bind to stainless-steel wires and that the bound

prions can be transmitted to transgenic mice expressing mutant human

α-synuclein.

■ PREVENTION AND THERAPEUTICS

There is no known effective therapy for preventing or treating CJD.

The finding that phenothiazines and acridines inhibit PrPSc formation

in cultured cells led to clinical studies of quinacrine in CJD patients.

Unfortunately, quinacrine failed to slow the rate of cognitive decline in

CJD, possibly because therapeutic concentrations of quinacrine were

not achieved in the brain. Although inhibition of the P-glycoprotein

(Pgp) transport system resulted in substantially increased quinacrine

levels in the brains of mice, the prion incubation times were not

extended by treatment with the drug. Whether such an approach can

be used to treat CJD remains to be established.

Like the acridines, anti-PrP antibodies have been shown to eliminate PrPSc from cultured cells. Additionally, such antibodies in mice,

either administered by injection or produced from a transgene, have

been shown to prevent prion disease when prions are introduced by

a peripheral route, such as intraperitoneal inoculation. Unfortunately,

the antibodies were ineffective in mice inoculated intracerebrally with

prions. Several drugs, including pentosan polysulfate as well as porphyrin and phenylhydrazine derivatives, delay the onset of disease in

animals inoculated intracerebrally with prions if the drugs are given

intracerebrally beginning soon after inoculation.

DIFFERENT PRIONS CAUSING OTHER

NEURODEGENERATIVE DISEASES

There is a rapidly expanding body of literature demonstrating that

besides PrP, other proteins including amyloid beta (Aβ), tau, α-synuclein,

and huntingtin can all refold into prions (Chap. 424). Experimental

and postmortem studies have shown that mutant transgenes in cultured cells or mice expressing the amyloid precursor protein (APP),

tau, or α-synuclein produce prions. Both cultured cells and Tg mice,

either spontaneously or after inoculation with prions from autopsy

specimens, support prion propagation. For example, transgenic mice

expressing mutant APP produce Aβ amyloid plaques containing fibrils

composed of the Aβ peptide that can be transmitted serially to Tg mice

and cultured cells. Similarly, tau aggregates in transgenic mice and cultured cells can initiate the aggregation of tau into fibrils that resemble

those found in neurofibrillary tangles and Pick bodies. Such tangles

have been found in AD, FTDs, Pick’s disease, as well as posttraumatic

brain injury (chronic traumatic encephalopathy) (Chap. 443), all of

which are thought to be caused by the prion isoforms of Aβ and/or tau.

In patients with advanced PD who received grafts of fetal substantia

nigral neurons, Lewy bodies containing β-sheet-rich α-synuclein were

identified in grafted cells ~10 years after transplantation, arguing for

the axonal transport of misfolded α-synuclein crossing into grafted

neurons, where it initiated aggregation of nascent α-synuclein into

fibrils that coalesced into Lewy bodies. These findings combined with

MSA studies argue that the synucleinopathies are caused by prions.

Brain homogenates from MSA patients injected into transgenic mice

transmitted lethal neurodegeneration in ~3 months; moreover, recombinant synuclein injected into wild-type mice initiated the deposition

of synuclein fibrils. Similar to the Tg mouse studies with Aβ and

tau, cultured cells expressing mutant α-synuclein also support prion

formation.

In summary, a wealth of evidence continues to accumulate arguing

that proteins causing AD, PD, FTDs, amyotrophic lateral sclerosis

(ALS), and even Huntington’s disease (HD) acquire alternative conformations that become self-propagating. Each of these NDs is thought to

be caused by the aberrant folding of a different protein that undergoes

a self-replicating conformational change to become a prion. Prions

explain many of the features that NDs have in common: (1) incidence

increases with age, (2) steady progression over years, (3) spread from

one region of the CNS to another, (4) protein deposits often but not

always consisting of amyloid fibrils, and (5) late onset of inherited

forms. Notably, amyloid plaques containing PrPSc are a nonobligatory

feature of PrP prion disease in humans and animals. Furthermore,

amyloid plaques in AD do not correlate with the level of dementia;

however, the level of soluble (oligomeric) Aβ peptide does correlate

with memory loss and other intellectual deficits.

■ FURTHER READING

Aoyagi A et al: Aβ and tau prion-like activities decline with longevity

in the Alzheimer’s disease human brain. Sci Transl Med 11:eaat8462,

2019.

Collinge J: Mammalian prions and their wider relevance in neurodegenerative diseases. Nature 539:217, 2016.

Kraus A et al: Structure of an infectious mammalian prion. bioRxiv

preprint, 2021.

Prusiner SB (ed): Prion Biology. Cold Spring Harbor, NY, Cold Spring

Harbor Laboratory Press, 2017.

Prusiner SB (ed): Prion Diseases. Cold Spring Harbor, NY, Cold

Spring Harbor Laboratory Press, 2017.

Prusiner SB et al: Evidence for α-synuclein prions causing multiple

system atrophy in humans with parkinsonism. Proc Natl Acad Sci

USA 112:E5308, 2015.

3423Ataxic Disorders CHAPTER

SYMMETRIC ATAXIA

439

Progressive and symmetric ataxia can be classified with respect to

onset as acute (over hours or days), subacute (weeks or months),

or chronic (months to years). Acute and reversible ataxias include

those caused by intoxication with alcohol, phenytoin, lithium,

barbiturates, and other drugs. Intoxication caused by toluene exposure, gasoline sniffing, glue sniffing, spray painting, or exposure to

methyl mercury or bismuth are additional causes of acute or subacute ataxia, as is treatment with cytotoxic chemotherapeutic drugs

such as fluorouracil and paclitaxel. Patients with a postinfectious

syndrome (especially after varicella) may develop gait ataxia and

mild dysarthria, both of which are reversible (Chap. 444). Rare

infectious causes of acquired ataxia include poliovirus, coxsackievirus, echovirus, Epstein-Barr virus, toxoplasmosis, Legionella,

and Lyme disease.

The subacute development of ataxia of gait over weeks to months

(degeneration of the cerebellar vermis) may be due to the combined

effects of alcoholism and malnutrition, particularly with deficiencies

of vitamins B1

 and B12. Hyponatremia has also been associated with

ataxia. Paraneoplastic cerebellar ataxia is associated with a number

of different tumors (and autoantibodies) such as breast and ovarian

cancers (anti-Yo), small-cell lung cancer (anti-PQ-type voltagegated calcium channel), and Hodgkin’s disease (anti-Tr) (Chap. 94).

Another paraneoplastic syndrome associated with myoclonus and

opsoclonus occurs with breast (anti-Ri) and lung cancers and neuroblastoma. Elevated serum anti-glutamic acid decarboxylase (GAD)

antibodies have been associated with a progressive ataxic syndrome

affecting speech and gait. For all of these paraneoplastic ataxias,

the neurologic syndrome may be the presenting symptom of the

cancer. Another immune-mediated progressive ataxia is associated

with antigliadin (and antiendomysium) antibodies and the human

leukocyte antigen (HLA) DQB1*

0201 haplotype; in some affected

patients, biopsy of the small intestine reveals villus atrophy consistent with gluten-sensitive enteropathy (Chap. 325). Finally, subacute

progressive ataxia may be caused by a prion disorder, especially

when an infectious etiology, such as transmission from contaminated human growth hormone, is responsible (Chap. 438).

Chronic symmetric gait ataxia suggests an inherited ataxia (discussed below), a metabolic disorder, or a chronic infection. Hypothyroidism must always be considered as a readily treatable and

reversible form of gait ataxia. Infectious diseases that can present

with ataxia are meningovascular syphilis and tabes dorsalis due to

degeneration of the posterior columns and spinocerebellar pathways in the spinal cord.

FOCAL ATAXIA

Acute focal ataxia commonly results from cerebrovascular disease, usually ischemic infarction or cerebellar hemorrhage. These

lesions typically produce cerebellar symptoms ipsilateral to the

TABLE 439-1 Etiology of Cerebellar Ataxia

SYMMETRIC AND PROGRESSIVE SIGNS FOCAL AND IPSILATERAL CEREBELLAR SIGNS

ACUTE (HOURS TO DAYS)

SUBACUTE (DAYS TO

WEEKS)

CHRONIC (MONTHS TO

YEARS) ACUTE (HOURS TO DAYS)

SUBACUTE (DAYS TO

WEEKS)

CHRONIC (MONTHS TO

YEARS)

Intoxication: alcohol,

lithium, phenytoin,

barbiturates (positive

history and toxicology

screen)

Acute viral cerebellitis

(CSF supportive of acute

viral infection)

Postinfection syndrome

Intoxication: mercury,

solvents, gasoline, glue

Cytotoxic

chemotherapeutic drugs

Alcoholic-nutritional

(vitamin B1

 and B12 deficiency)

Lyme disease

Paraneoplastic syndrome

Antigliadin antibody

syndrome

Hypothyroidism

Inherited diseases

Tabes dorsalis (tertiary

syphilis)

Phenytoin toxicity

Amiodarone

Vascular: cerebellar

infarction, hemorrhage, or

subdural hematoma

Infectious: cerebellar

abscess (mass lesion on

MRI/CT, history in support

of lesion)

Neoplastic: cerebellar

glioma or metastatic

tumor (positive for

neoplasm on MRI/CT)

Demyelinating: multiple

sclerosis (history, CSF,

and MRI are consistent)

AIDS-related multifocal

leukoencephalopathy

(positive HIV test and

CD4+ cell count for AIDS)

Stable gliosis secondary

to vascular lesion or

demyelinating plaque

(stable lesion on MRI/

CT older than several

months)

Congenital lesion:

Chiari or DandyWalker malformations

(malformation noted on

MRI/CT)

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.

injured cerebellum and may be associated with an impaired level

of consciousness due to brainstem compression and increased

intracranial pressure; ipsilateral pontine signs, including sixth and

seventh nerve palsies, may be present. Focal and worsening signs of

acute ataxia should also prompt consideration of a posterior fossa

subdural hematoma, bacterial abscess, or primary or metastatic

cerebellar tumor. CT or MRI studies will reveal clinically significant

processes of this type. Many of these lesions represent true neurologic emergencies, as sudden herniation, either rostrally through

the tentorium or caudal herniation of cerebellar tonsils through

the foramen magnum, can occur and is usually devastating. Acute

surgical decompression may be required (Chap. 301). Lymphoma

or progressive multifocal leukoencephalopathy (PML) in a patient

with AIDS may present with an acute or subacute focal cerebellar

syndrome. Chronic etiologies of progressive ataxia include multiple

sclerosis (Chap. 444) and congenital lesions such as a Chiari malformation (Chap. 442) or a congenital cyst of the posterior fossa

(Dandy-Walker syndrome).

THE INHERITED ATAXIAS

Inherited ataxias may show autosomal dominant, autosomal recessive,

or maternal (mitochondrial) modes of inheritance. A genomic classification (Table 439-2)1

 has now largely superseded previous ones based

on clinical expression alone.

Although the clinical manifestations and neuropathologic findings of

cerebellar disease dominate the clinical picture, there may also be characteristic changes in the basal ganglia, brainstem, spinal cord, optic nerves,

retina, and peripheral nerves. In large families with dominantly inherited

ataxias, many gradations are observed from purely cerebellar manifestations to mixed cerebellar and brainstem disorders, cerebellar and basal

ganglia syndromes, and spinal cord or peripheral nerve disease. Rarely,

dementia is present as well. The clinical picture may be homogeneous

within a family with dominantly inherited ataxia, but sometimes most

affected family members show one characteristic syndrome, while one

or several members have an entirely different phenotype.

■ AUTOSOMAL DOMINANT ATAXIAS

The autosomal spinocerebellar ataxias (SCAs) include SCA types 1

through 43, dentatorubropallidoluysian atrophy (DRPLA), and episodic ataxia (EA) types 1 to 7 (Table 439-2). SCA1, SCA2, SCA3

(Machado-Joseph disease [MJD]), SCA6, SCA7, and SCA17 are caused

by CAG triplet repeat expansions in different genes. SCA8 is due to an

untranslated CTG repeat expansion, SCA12 is linked to an untranslated

CAG repeat, and SCA10 is caused by an untranslated pentanucleotide

repeat. The clinical phenotypes of these SCAs overlap. The genotype

1

Table 439-2 can be found online at www.accessmedicine.com.