3451 Diseases of the Spinal Cord CHAPTER 442

additional symptoms of an immune-mediated disease. Transverse

myelitis refers to a pattern of extensive spinal cord injury, clinically

manifest as bilateral sensory symptoms, unilateral or bilateral weakness, and bladder and/or bowel disturbance. In most of the developed

world MS is the most common inflammatory cause of an acute myelitis

but involvement is usually partial and not transverse. Recurrent episodes of myelitis are usually due to one of the immune-mediated diseases or to infection with herpes simplex virus (HSV) type 2 (below).

MULTIPLE SCLEROSIS MS may present with acute myelitis, particularly in individuals of Asian or African ancestry. In whites, MS attacks

rarely cause a transverse myelopathy (i.e., attacks of bilateral sensory

disturbances, unilateral or bilateral weakness, and bladder or bowel

symptoms), but MS is among the most common causes of a partial cord

syndrome. MRI findings in MS-associated myelitis typically consist

of mild swelling of the cord and diffuse or multifocal “shoddy” areas

of abnormal signal on T2-weighted sequences. Contrast enhancement, indicating disruption in the blood-brain barrier associated with

inflammation, is present in many acute cases. In one study 68% of

patients presenting with partial myelitis developed MS after a mean

follow-up of 4 years; risk factors for conversion to MS included age <40

years; inflammatory CSF, and >3 periventricular lesions on brain MRI.

Treatment of acute episodes of MS-associated myelitis consists

of intravenous methylprednisolone (500 mg qd for 3 days) followed

by oral prednisone (1 mg/kg per day for several weeks, then gradual

taper). A course of plasma exchange may be indicated for severe cases

if glucocorticoids are ineffective. MS is discussed in Chap. 444.

NEUROMYELITIS OPTICA NMO is an immune-mediated demyelinating disorder consisting of a severe myelopathy that is typically

longitudinally extensive, meaning that the lesion spans three or more

vertebral segments. NMO is associated with optic neuritis that is often

bilateral and may precede or follow myelitis by weeks or months, and

also by brainstem and, in some cases, hypothalamic or focal cerebral

white matter involvement. Recurrent myelitis without optic nerve

or other involvement can also occur in NMO. CSF studies reveal a

variable mononuclear pleocytosis of up to several hundred cells per

microliter (higher than in typical MS) with occasional cases showing

polymorphonuclear predominant pattern; oligoclonal bands are present in <20% of NMO cases. Diagnostic serum autoantibodies against

the water channel protein aquaporin-4 (AQP-4) are present in 90%

of patients with NMO; in some AQP-4 negative cases autoantibodies

against the CNS myelin protein myelin oligodendrocyte glycoprotein

(MOG) are found. NMO has also been associated with SLE (see below)

as well as with other systemic autoimmune diseases; rare cases are

paraneoplastic. Acute relapses of NMO are treated with glucocorticoids

and, for severe or refractory cases, plasma exchange. Three monoclonal

antibodies are now available for prophylactic treatment: eculizumab, a

terminal complement inhibitor; inebilizumab, a B-cell depleter; and

satralizumab, an IL-6 receptor blocker. Off-label use of azathioprine,

mycophenolate, or rituximab are other options. Treatment for 5 years

or longer is generally recommended. NMO is discussed in Chap. 445.

SARCOIDOSIS Sarcoid myelopathy may present as a slowly progressive

or relapsing disorder. Clinically, sensory involvement often predominates. MRI reveals edematous swelling of the spinal cord that may

mimic tumor and subpial gadolinium enhancement of active lesions

typically along the dorsal surface of the cord. In some cases nodular

enhancing lesions can be seen; lesions may be single or multiple, and

on axial images enhancement of the central cord is often present.

The typical CSF profile consists of a mild lymphocyte-predominant

pleocytosis and elevated protein level; in a minority of cases, reduced

glucose and oligoclonal bands are found. The diagnosis is particularly

difficult when systemic manifestations of sarcoid are minor or absent

(nearly 50% of cases) or when other typical neurologic manifestations

of the disease, such as cranial neuropathy, hypothalamic involvement,

or meningeal enhancement visualized by MRI, are lacking. A slit-lamp

examination of the eye to search for uveitis, chest x-ray and CT to

assess pulmonary involvement and mediastinal lymphadenopathy,

serum or CSF angiotensin-converting enzyme (ACE; lacks specificity

and values are elevated in only a minority of cases), serum calcium, and

a gallium scan may assist in the diagnosis. Initial treatment is with high

doses of glucocorticoids, which need to be administered long term and

tapered slowly while monitoring resolution of clinical and MRI signs

of active disease; relapses are managed with high-dose glucocorticoids

plus a steroid-sparing immunosuppressant drug (typically mycophenolate mofetil, azathioprine, or methotrexate), or with the tumor necrosis

factor α-inhibitor infliximab. Sarcoidosis is discussed in Chap. 367.

SYSTEMIC IMMUNE-MEDIATED DISORDERS Myelitis occurs in a small

number of patients with SLE, many cases of which are associated with

antibodies to AQP-4 and satisfy diagnostic criteria for NMO (discussed

above). These patients are at high risk of developing future episodes of

myelitis and/or optic neuritis. In others the etiology of SLE-associated

myelitis is uncertain; antiphospholipid antibodies have been suggested

to play a role; however, the presence of these antibodies appears to be

no more frequent in SLE patients with and without myelitis. The CSF

in NMO-associated myelitis typically shows a pleocytosis often with

polymorphonuclear leukocytes, and no oligoclonal bands; in cases not

due to NMO a mild lymphocytic pleocytosis and oligoclonal bands are

variable findings. Although there are no systematic trials of therapy for

SLE myelitis, based on limited data high-dose glucocorticoids followed

by cyclophosphamide have been recommended. Severe episodes that

do not initially respond to glucocorticoids are often treated with a

course of plasma exchange. Sjögren’s syndrome (Chap. 361) can also be

associated with NMO and also with cases of chronic progressive myelopathy. Other immune-mediated myelitides include Behçet’s disease

(Chap. 364), antiphospholipid antibody syndrome (Chap. 357), mixed

connective tissue disease (Chap. 360), and vasculitis related to polyarteritis nodosa, perinuclear antineutrophilic cytoplasmic (p-ANCA)

antibodies, or primary central nervous system vasculitis (Chap. 363).

Occasional cases of myelitis, often accompanied by other manifestations that can include encephalitis or optic neuritis, have been recently

associated with autoantibodies against glial fibrillary acidic protein

(GFAP) (Chap. 444). Other rare etiologies are chronic lymphocytic

inflammation with pontine perivascular enhancement responsive to

steroids (CLIPPERS), and Erdheim-Chester disease producing inflammatory masslike lesions that can be intramedullary or extraaxial and

compressive.

POSTINFECTIOUS MYELITIS Many cases of myelitis, termed postinfectious or postvaccinal, follow an infection or vaccination. Numerous

organisms have been implicated, including Epstein-Barr virus (EBV),

cytomegalovirus (CMV), mycoplasma, influenza, measles, varicella,

mumps, and yellow fever. As in the related disorder acute disseminated

encephalomyelitis (Chap. 444), postinfectious myelitis often begins as

the patient appears to be recovering from an acute febrile infection,

or in the subsequent days or weeks, but an infectious agent cannot be

isolated from the nervous system or CSF. Serum anti-MOG antibodies

are present acutely in about half of cases. The presumption is that the

myelitis represents an autoimmune disorder triggered by infection and

is not due to direct infection of the spinal cord. No randomized controlled trials of therapy exist; treatment is usually with glucocorticoids

or, in fulminant cases, plasma exchange.

ACUTE INFECTIOUS MYELITIS Many viruses have been associated

with an acute myelitis that is infectious in nature rather than postinfectious. Nonetheless, the two processes are often difficult to distinguish.

Herpes zoster is the best characterized viral myelitis, but HSV types 1

and 2, EBV, CMV, and rabies virus are other well-described causes and

Zika virus has also been recognized as a cause of infectious myelitis.

HSV-2 (and less commonly HSV-1) produces a distinctive syndrome

of recurrent sacral cauda equina neuritis in association with outbreaks

of genital herpes (Elsberg’s syndrome). Poliomyelitis is the prototypic

viral myelitis, but it is more or less restricted to the anterior gray matter

of the cord containing the spinal motoneurons. A polio-like syndrome

can also be caused by a large number of enteroviruses (including

enterovirus A-71 and coxsackie), and with Japanese encephalitis and

other flaviviruses such as West Nile virus. Beginning in 2012, cases

of acute flaccid paralysis in children and adolescents have appeared

3452 PART 13 Neurologic Disorders

associated with enterovirus A-71 and D-68 infection. Chronic viral

myelitic infections, such as those due to HIV or human T-cell lymphotropic virus type 1 (HTLV-1), are discussed below.

Bacterial and mycobacterial myelitis (most are essentially abscesses)

are less common than viral causes and much less frequent than cerebral

bacterial abscess. Almost any pathogenic species may be responsible,

including Borrelia burgdorferi (Lyme disease), Listeria monocytogenes,

Mycobacterium tuberculosis, and Treponema pallidum (syphilis). Mycoplasma pneumoniae may be a cause of myelitis, but its status is uncertain because many cases are more properly classified as postinfectious.

Schistosomiasis (Chap. 234) is an important cause of parasitic

myelitis in endemic areas. The process is intensely inflammatory and

granulomatous, caused by a local response to tissue-digesting enzymes

from the ova of the parasite, typically Schistosoma haematobium or

Schistosoma mansoni. Toxoplasmosis (Chap. 228) can occasionally

cause a focal myelopathy, and this diagnosis should especially be considered in patients with AIDS (Chap. 202). Cysticercosis (Chap. 235) is

another consideration, although myelitis from this helminth is far less

common than parenchymal brain or meningeal involvement.

In cases of suspected viral myelitis, it may be appropriate to begin

specific therapy pending laboratory confirmation. Herpes zoster, HSV,

and EBV myelitis are treated with intravenous acyclovir (10 mg/kg

q8h) or oral valacyclovir (2 g tid) for 10–14 days; CMV is treated with

ganciclovir (5 mg/kg IV bid) plus foscarnet (60 mg/kg IV tid) or cidofovir (5 mg/kg per week for 2 weeks).

High-Voltage Electrical Injury Spinal cord injuries are prominent following electrocution from lightning strikes or other accidental

electrical exposures. The syndrome consists of transient weakness

acutely (often with an altered sensorium and focal cerebral disturbances), sometimes followed several days or even weeks later by a myelopathy that can be severe and permanent. This is a rare injury type,

and limited data incriminate a vascular pathology involving the anterior spinal artery and its branches in some cases. Therapy is supportive.

CHRONIC MYELOPATHIES

■ SPONDYLOTIC MYELOPATHY

Spondylotic myelopathy is the most common cause of myelopathy and

of gait difficulty in the elderly, accounting for more than half of nontraumatic spinal cord injuries in some series. Neck and shoulder pain

with stiffness are early symptoms; impingement of bone and soft tissue

overgrowth on nerve roots results in radicular arm pain, most often

in a C5 or C6 distribution. Compression of the cervical cord, which

occurs in fewer than one-third of cases, produces a slowly progressive

spastic paraparesis, at times asymmetric and often accompanied by

paresthesias in the feet and hands. Vibratory sense is diminished in the

legs, there is a Romberg sign, and occasionally there is a sensory level

for vibration or pinprick on the upper thorax. In some cases, coughing

or straining produces leg weakness or radiating arm or shoulder pain.

Dermatomal sensory loss in the arms, atrophy of intrinsic hand muscles, increased deep-tendon reflexes in the legs, and extensor plantar

responses are common. Urinary urgency or incontinence occurs in

advanced cases, but there are many alternative causes of these problems

in older individuals. A tendon reflex in the arms is often diminished

at some level; most often at the biceps (C5-C6). In individual cases,

radicular, myelopathic, or combined signs may predominate. The diagnosis should be considered in appropriate cases of progressive cervical

myelopathy, paresthesias of the feet and hands, or wasting of the hands.

Diagnosis is usually made by MRI and may be suspected from CT

images; plain x-rays are less helpful. Extrinsic cord compression and

deformation are appreciated on axial MRI views, and T2-weighted

sequences may reveal areas of high signal intensity within the cord

adjacent to the site of compression. A cervical collar may be helpful

in milder cases, but the likelihood of progression of medically treated

myelopathy is high, estimated at 8% over 1 year. Definitive therapy

consists of surgical decompression, either posterior laminectomy or

an anterior approach with resection of the protruded disk and bony

material. Cervical spondylosis and related degenerative diseases of

the spine are discussed in Chap. 17.

■ VASCULAR MALFORMATIONS OF THE

CORD AND DURA

Vascular malformations, comprising ~4% of all mass lesions of the

cord and overlying dura, are treatable causes of progressive myelopathy. Most common are fistulas located within the dura or posteriorly

along the surface of the cord. Most dural arteriovenous (AV) fistulas

are located at or below the midthoracic level, usually consisting of a

direct connection between a radicular feeding artery in the nerve root

sleeve with dural veins. The typical presentation is a middle-aged man

with a progressive myelopathy that worsens slowly or intermittently

and may have periods of remission, sometimes mimicking MS. Acute

deterioration due to hemorrhage into the spinal cord (hematomyelia)

or subarachnoid space may also occur but is rare. In many cases,

progression results from local ischemia and edema due to venous

congestion. Most patients have incomplete sensory, motor, and bladder disturbances. The motor disorder may predominate and produce a

mixture of upper and restricted lower motor neuron signs, simulating

amyotrophic lateral sclerosis (ALS). Pain over the dorsal spine, dysesthesias, or radicular pain may be present. Other symptoms suggestive

of AV malformation (AVM) or dural fistula include intermittent

claudication; symptoms that change with posture, exertion, Valsalva

maneuver, or menses; and fever.

Less commonly, AVM disorders are intramedullary rather than

dural. One unusual disorder is a progressive thoracic myelopathy with

paraparesis developing over weeks or months, characterized pathologically by abnormally thick, hyalinized vessels within the cord (subacute

necrotic myelopathy or Foix-Alajouanine syndrome).

Spinal bruits are infrequent but may be sought at rest and after

exercise in suspected cases. A vascular nevus on the overlying skin

may indicate an underlying vascular malformation as occurs with

Klippel-Trenaunay-Weber syndrome. MR angiography and CT angiography can detect the draining vessels of many AVMs (Fig. 442-6).

Definitive diagnosis requires selective spinal angiography, which

defines the feeding vessels and the extent of the malformation. Treatment is tailored to the anatomy and location of the lesion, and generally

consists of microsurgical resection, endovascular embolization of the

major feeding vessels, or a combination of the two approaches.

FIGURE 442-6 Arteriovenous malformation. Sagittal magnetic resonance scans

of the thoracic spinal cord: T2 fast spin-echo technique (left) and T1 postcontrast

image (right). On the T2-weighted image (left), abnormally high signal intensity is

noted in the central aspect of the spinal cord (arrowheads). Numerous punctate

flow voids indent the dorsal and ventral spinal cord (arrow). These represent the

abnormally dilated venous plexus supplied by a dural arteriovenous fistula. After

contrast administration (right), multiple, serpentine, enhancing veins (arrows) on

the ventral and dorsal aspect of the thoracic spinal cord are visualized, diagnostic

of arteriovenous malformation. This patient was a 54-year-old man with a 4-year

history of progressive paraparesis.

3453 Diseases of the Spinal Cord CHAPTER 442

■ RETROVIRUS-ASSOCIATED MYELOPATHIES

The myelopathy associated with HTLV-1, formerly called tropical

spastic paraparesis, is a slowly progressive spastic syndrome with variable sensory and bladder disturbance. Approximately half of patients

have mild back or leg pain. The neurologic signs may be asymmetric,

often lacking a well-defined sensory level; the only sign in the arms

may be hyperreflexia after several years of illness. The onset is usually

insidious, and the tempo of progression of the illness occurs at a variable rate; in one study, median time for progression to cane-, walker-,

or wheelchair-dependent state was 6, 13, and 21 years, respectively.

Progression appears to be more rapid in older patients and those with

higher viral loads. Diagnosis is made by demonstration of HTLV-1-

specific antibody in serum by enzyme-linked immunosorbent assay

(ELISA), confirmed by radioimmunoprecipitation or Western blot

analysis. Especially in endemic areas, a finding of HTLV-1 seropositivity in a patient with myelopathy does not necessarily prove that

HTLV-1 is causative. The CSF/serum antibody index may provide

support by establishing intrathecal synthesis of antibodies, including

oligoclonal antibodies, favoring HTVL-1 myelopathy over asymptomatic carriage. Measuring proviral DNA by polymerase chain reaction

(PCR) in serum and CSF cells can be useful as an ancillary part of diagnosis. The pathogenesis of the myelopathy is uncertain. It could result

from an immune response directed against HTLV-1 antigens in the

nervous system, or alternatively to secondary autoimmunity triggered

by the viral infection. There is no proven effective treatment. Based

on limited evidence, the use of chronic low-dose oral glucocorticoids

can be tried; interferon is of uncertain value, and antiviral treatment is

ineffective. Symptomatic therapy for spasticity and bladder symptoms

may be helpful.

A progressive myelopathy can also result from HIV infection

(Chap. 197). It is characterized by vacuolar degeneration of the posterior and lateral tracts, resembling subacute combined degeneration

(see below).

SYRINGOMYELIA

Syringomyelia is a developmental cavity in the cervical cord that may

enlarge and produce progressive myelopathy or may remain asymptomatic. Symptoms begin insidiously in adolescence or early adulthood,

progress irregularly, and may undergo spontaneous arrest for several

years. Many young patients acquire a cervical-thoracic scoliosis. More

than half of all cases are associated with Chiari type 1 malformations

in which the cerebellar tonsils protrude through the foramen magnum and into the cervical spinal canal. The pathophysiology of syrinx

expansion is controversial, but some interference with the normal flow

of CSF seems likely, perhaps by the Chiari malformation. Acquired cavitations of the cord in areas of necrosis are also termed syrinx cavities;

these follow trauma, myelitis, necrotic spinal cord tumors, and chronic

arachnoiditis due to tuberculosis and other etiologies.

The presentation is a central cord syndrome consisting of a regional

dissociated sensory loss (loss of pain and temperature sensation with

sparing of touch and vibration) and areflexic weakness in the upper

limbs. The sensory deficit has a distribution that is “suspended” over

the nape of the neck, shoulders, and upper arms (cape distribution) or

in the hands. Most cases begin asymmetrically with unilateral sensory

loss in the hands that leads to injuries and burns that are not appreciated by the patient. Muscle wasting in the lower neck, shoulders, arms,

and hands with asymmetric or absent reflexes in the arms reflects

expansion of the cavity in the gray matter of the cord. As the cavity

enlarges and compresses the long tracts, spasticity and weakness of the

legs, bladder and bowel dysfunction, and Horner’s syndrome appear.

Some patients develop facial numbness and sensory loss from damage

to the descending tract of the trigeminal nerve (C2 level or above). In

cases with Chiari malformations, cough-induced headache and neck,

arm, or facial pain may be reported. Extension of the syrinx into the

medulla, syringobulbia, causes palatal or vocal cord paralysis, dysarthria, horizontal or vertical nystagmus, episodic dizziness or vertigo,

and tongue weakness with atrophy.

MRI accurately identifies developmental and acquired syrinx cavities and their associated spinal cord enlargement (Fig. 442-7). Images

of the brain and the entire spinal cord should be obtained to delineate

the full longitudinal extent of the syrinx, assess posterior fossa structures for the Chiari malformation, and determine whether hydrocephalus is present.

TREATMENT

Syringomyelia

Treatment of syringomyelia is generally unsatisfactory. The Chiari

tonsillar herniation may be decompressed, generally by suboccipital

craniectomy, upper cervical laminectomy, and placement of a dural

graft. Fourth ventricular outflow is reestablished by this procedure.

If the syrinx cavity is large, some surgeons recommend direct

decompression or drainage, but the added benefit of this procedure

is uncertain, and complications are common. With Chiari malformations, shunting of hydrocephalus generally precedes any attempt

to correct the syrinx. Surgery may stabilize the neurologic deficit,

and some patients improve. Patients with few symptoms and signs

from the syrinx do not require surgery and are followed by serial

clinical and imaging examinations.

Syrinx cavities secondary to trauma or infection, if symptomatic,

are treated with a decompression and drainage procedure in which

a small shunt is inserted between the cavity and subarachnoid

space; alternatively, the cavity can be fenestrated. Cases due to

intramedullary spinal cord tumor are generally managed by resection of the tumor.

■ CHRONIC MYELOPATHY OF MULTIPLE

SCLEROSIS

A chronic progressive myelopathy is the most frequent cause of disability in both primary progressive and secondary progressive forms

of MS. Involvement is typically bilateral but asymmetric and produces

motor, sensory, and bladder/bowel disturbances. Fixed motor disability appears to result from extensive loss of axons in the corticospinal

tracts. Diagnosis is facilitated by identification of earlier attacks such

as optic neuritis. MRI, CSF, and evoked-response testing are confirmatory. Treatment with ocrelizumab, an anti-CD20 B-cell monoclonal

antibody, is effective in patients with primary progressive MS, and

disease-modifying therapy is also indicated in patients with secondary

FIGURE 442-7 Magnetic resonance imaging of syringomyelia associated with a

Chiari malformation. Sagittal T1-weighted image through the cervical and upper

thoracic spine demonstrates descent of the cerebellar tonsils below the level of the

foramen magnum (black arrows). Within the substance of the cervical and thoracic

spinal cord, a cerebrospinal fluid collection dilates the central canal (white arrows).

3454 PART 13 Neurologic Disorders

progressive MS who have clinical or MRI evidence of active disease.

MS is discussed in Chap. 444.

■ SUBACUTE COMBINED DEGENERATION

(VITAMIN B12 DEFICIENCY)

This treatable myelopathy presents with subacute paresthesias in the

hands and feet, loss of vibration and position sensation, and a progressive spastic and ataxic weakness. Loss of reflexes due to an associated

peripheral neuropathy in a patient who also has Babinski signs is a

helpful diagnostic clue. Optic atrophy and irritability or other cognitive changes may be prominent in advanced cases and are occasionally

the presenting symptoms. The myelopathy of subacute combined

degeneration tends to be diffuse rather than focal; signs are generally

symmetric and reflect predominant involvement of the posterior and

lateral tracts, including Romberg sign. Causes include dietary deficiency, especially in vegans, and gastric malabsorption syndromes

including pernicious anemia (Chap. 99). The diagnosis is confirmed

by the finding of macrocytic red blood cells, a low serum B12 concentration, and elevated serum levels of homocysteine and methylmalonic

acid. Treatment is by replacement therapy, beginning with 1000 μg of

intramuscular vitamin B12 daily for 5 days and then continued as a once

monthly maintenance dose; oral maintenance is also reasonable, except

in cases of pernicious anemia.

Two closely related conditions deserve mention here. The first is

folate deficiency–associated myelopathy, now only rarely seen since

widespread programs of dietary fortification with folate have been

implemented. A second is due to inhalation with nitrous oxide (laughing gas), an irreversible inhibitor of vitamin B12, which also produces a

myelopathy identical to subacute combined degeneration. Exposure to

nitrous oxide may occur during dental or surgical procedures or from

recreational inhalation (“doing whippets”).

■ HYPOCUPRIC MYELOPATHY

This myelopathy is similar to subacute combined degeneration

(described above), except serum levels of B12 are normal. Low levels of

serum copper are found, and often there is also a low level of serum

ceruloplasmin. Some cases follow gastrointestinal procedures, particularly bariatric surgery, that result in impaired copper absorption; others

have been associated with excess zinc from health food supplements or

in the past zinc-containing denture creams, all of which impair copper

absorption via induction of metallothionein, a copper-binding protein.

Many cases are idiopathic. There is often a coexisting anemia. Improvement or at least stabilization may be expected with reconstitution of

copper stores by oral supplementation.

■ TABES DORSALIS

The classic syphilitic syndromes of tabes dorsalis and meningovascular

inflammation of the spinal cord are now less frequent than in the past

but must be considered in the differential diagnosis of spinal cord disorders. The characteristic symptoms of tabes are fleeting and repetitive

lancinating pains, primarily in the legs or less often in the back, thorax,

abdomen, arms, and face. Ataxia of the legs and gait due to loss of

position sense occurs in half of patients. Paresthesias, bladder disturbances, and acute abdominal pain with vomiting (visceral crisis) occur

in 15–30% of patients. The cardinal signs of tabes are loss of reflexes in

the legs; impaired position and vibratory sense; Romberg sign; and,

in almost all cases, bilateral Argyll Robertson pupils, which fail to

constrict to light but accommodate. Diabetic polyradiculopathy may

simulate this condition. Treatment of tabes dorsalis and other forms

of neurosyphilis consists of penicillin G administered intravenously,

or intramuscularly in combination with oral probenecid (Chap. 182).

■ HEREDITARY SPASTIC PARAPLEGIA

Many cases of slowly progressive myelopathy are genetic in origin

(Chap. 437). More than 80 different causative loci have been identified,

including autosomal dominant, autosomal recessive, and X-linked

forms. Especially for the recessive and X-linked forms, a family history of myelopathy may be lacking. Most patients present with almost

imperceptibly progressive spasticity and weakness in the legs, usually

but not always symmetrical. Sensory symptoms and signs are absent

or mild, but sphincter disturbances may be present. In some families,

additional neurologic signs are prominent, including nystagmus,

ataxia, or optic atrophy. The onset may be as early as the first year of

life or as late as middle adulthood. Only symptomatic therapies are

available.

PRIMARY LATERAL SCLEROSIS

This is a mid- to late-life onset degenerative disorder characterized by

progressive spasticity with weakness, eventually accompanied by dysarthria and dysphonia; bladder symptoms occur in approximately half

of patients. Sensory function is spared. The disorder resembles ALS

and is considered a variant of the motor neuron degenerations, but

without the characteristic lower motor neuron disturbance and with

typically a slower progression. Some cases may represent late-onset

cases of familial spastic paraplegia, particularly autosomal recessive or

X-linked varieties in which a family history may be absent. (See also

Chap. 437.)

■ ADRENOMYELONEUROPATHY

This X-linked disorder is a variant of adrenoleukodystrophy (ALD).

Most affected males have a history of adrenal insufficiency and then

develop a progressive spastic (or ataxic) paraparesis beginning in

early or sometimes middle adulthood; some patients also have a mild

peripheral neuropathy. Female heterozygotes may develop a slower,

insidiously progressive spastic myelopathy beginning later in adulthood and without adrenal insufficiency. Diagnosis is usually made

by demonstration of elevated levels of very-long-chain fatty acids in

plasma and in cultured fibroblasts. The responsible gene encodes the

adrenoleukodystrophy protein (ALDP), a peroxisomal membrane

transporter involved in carrying long-chain fatty acids to peroxisomes

for degradation. Corticosteroid replacement is indicated if hypoadrenalism is present. Allogeneic bone marrow transplantation has been

successful in slowing progression of cognitive decline in some patients

with ALD treated early in their disease but appears to be ineffective for

the myelopathy of ALD. Nutritional supplements (Lorenzo’s oil) have

also been attempted for this condition without evidence of efficacy.

■ CANCER-RELATED SYNDROMES

Cancer-related causes of chronic myelopathy, besides the common

neoplastic compressive myelopathy discussed earlier, include radiation

injury (Chap. 90), and a myelopathy resembling subacute combined

degeneration that can follow intrathecal administration of methotrexate (a folate antagonist). Rare paraneoplastic myelopathies are most

often associated with lung cancer and anti-amphiphysin (also breast),

anti-collapsin response mediator 5 (CRMP5) (also lymphoma), or

anti-Hu antibodies (Chap. 94). Another uncommon lymphomaassociated paraneoplastic syndrome is a progressive flaccid paresis with

destruction of anterior horn cells. NMO with aquaporin-4 antibodies

(Chap. 445) can also rarely be paraneoplastic in origin. Metastases to

the cord are probably more common than any of these disorders in

patients with cancer.

■ OTHER CHRONIC MYELOPATHIES

Tethered cord syndrome is a developmental disorder of the lower spinal

cord and nerve roots that rarely presents in adulthood as low back pain

accompanied by a progressive lower spinal cord and/or nerve root

syndrome. Some patients have a small leg or foot deformity indicating

a long-standing process, and in others, a dimple, patch of hair, or sinus

tract on the skin overlying the lower back is the clue to a congenital

lesion. Diagnosis is made by MRI, which demonstrates a low-lying

conus medullaris and thickened filum terminale. The MRI may also

reveal diastematomyelia (division of the lower spinal cord into two

halves), lipomas, cysts, or other congenital abnormalities of the lower

spine coexisting with the tethered cord. Treatment is with surgical

release.

There are a number of rare toxic causes of spastic myelopathy,

including lathyrism due to ingestion of chickpeas containing the

excitotoxin β-N-oxalylamino-L-alanine (BOAA), seen primarily in

the developing world or during famines, and Konzo due to ingestion

of the cyanogen-containing casava plant found in sub-Saharan Africa.

3455 Diseases of the Spinal Cord CHAPTER 442

Often, a cause of intrinsic myelopathy can be identified only

through periodic reassessment.

REHABILITATION OF SPINAL

CORD DISORDERS

The prospects for recovery from an acute destructive spinal cord

lesion fade after ~6 months. There are currently no effective means

to promote repair of injured spinal cord tissue; promising but entirely

experimental approaches include the use of factors that influence

reinnervation by axons of the corticospinal tract, nerve and neural

sheath graft bridges, forms of electrical stimulation at the site of injury,

and the local introduction of stem cells. The disability associated with

irreversible spinal cord damage is determined primarily by the level of

the lesion and by whether the disturbance in function is complete or

incomplete (Table 442-4). Even a complete high cervical cord lesion

may be compatible with a productive life. The primary goals are development of a rehabilitation plan framed by realistic expectations and

attention to the neurologic, medical, and psychological complications

that commonly arise.

Many of the usual symptoms associated with medical illnesses,

especially somatic and visceral pain, may be lacking because of the

destruction of afferent pain pathways. Unexplained fever, worsening

of spasticity, or deterioration in neurologic function should prompt a

search for infection, thrombophlebitis, or an intraabdominal pathology. The loss of normal thermoregulation and inability to maintain

normal body temperature can produce recurrent fever (quadriplegic

fever), although most episodes of fever are due to infection of the urinary tract, lung, skin, or bone.

Bladder dysfunction generally results from loss of supraspinal

innervation of the detrusor muscle of the bladder wall and the sphincter musculature. Detrusor spasticity is treated with anticholinergic

drugs (oxybutynin, 2.5–5 mg qid) or tricyclic antidepressants with

anticholinergic properties (imipramine, 25–200 mg/d). Failure of the

sphincter muscle to relax during bladder emptying (urinary dyssynergia)

may be managed with the α-adrenergic blocking agent terazosin

hydrochloride (1–2 mg tid or qid), with intermittent catheterization,

or, if that is not feasible, by use of a condom catheter in men or a permanent indwelling catheter. Surgical options include the creation of an

artificial bladder by isolating a segment of intestine that can be catheterized intermittently (enterocystoplasty) or can drain continuously to

an external appliance (urinary conduit). Bladder areflexia due to acute

spinal shock or conus lesions is best treated by catheterization. Bowel

regimens and disimpaction are necessary in most patients to ensure at

least biweekly evacuation and avoid colonic distention or obstruction.

Patients with acute cord injury are at risk for venous thrombosis and

pulmonary embolism. Use of calf-compression devices and anticoagulation

with low-molecular-weight heparin are recommended. In cases of persistent paralysis, anticoagulation should probably be continued for 3 months.

Prophylaxis against decubitus ulcers should involve frequent changes

in position in a chair or bed, the use of special mattresses, and cushioning of areas where pressure sores often develop, such as the sacral prominence and heels. Early treatment of ulcers with careful cleansing, surgical

or enzyme debridement of necrotic tissue, and appropriate dressing and

drainage may prevent infection of adjacent soft tissue or bone.

Spasticity is aided by stretching exercises to maintain mobility of

joints. Drug treatment is effective but may result in reduced function,

as some patients depend on spasticity as an aid to stand, transfer, or

walk. Baclofen (up to 240 mg/d in divided doses) is effective; it acts

by facilitating γ-aminobutyric acid–mediated inhibition of motor

reflex arcs. Diazepam acts by a similar mechanism and is useful

for leg spasms that interrupt sleep (2–4 mg at bedtime). Tizanidine

(2–8 mg tid), an α2

 adrenergic agonist that increases presynaptic

inhibition of motor neurons, is another option. For nonambulatory

patients, the direct muscle inhibitor dantrolene (25–100 mg qid) may

be used, but it is potentially hepatotoxic. In refractory cases, intrathecal baclofen administered via an implanted pump, botulinum toxin

injections, or dorsal rhizotomy may be required to control spasticity.

Despite the loss of sensory function, many patients with spinal cord

injury experience chronic pain sufficient to diminish their quality of

life. Randomized controlled studies indicate that gabapentin or pregabalin is useful in this setting. Epidural electrical stimulation and intrathecal infusion of pain medications have been tried with some success.

Management of chronic pain is discussed in Chap. 13.

A paroxysmal autonomic hyperreflexia may occur following lesions

above the major splanchnic sympathetic outflow at T6. Headache,

flushing, and diaphoresis above the level of the lesion, as well as hypertension with bradycardia or tachycardia, are the major symptoms. The

trigger is typically a noxious stimulus—for example, bladder or bowel

distention, a urinary tract infection, or a decubitus ulcer—below the

level of the cord lesion. Treatment consists of removal of offending

stimuli; ganglionic blocking agents (mecamylamine, 2.5–5 mg) or

other short-acting antihypertensive drugs are useful in some patients.

Attention to these details allows longevity and a productive life for

patients with complete transverse myelopathies.

■ FURTHER READING

Badhiwala JH et al: Degenerative cervical myelopathy—update and

future directions. Nat Rev Neurol 16:108, 2020.

Barreras P et al: Clinical biomarkers differentiate myelitis from vascular and other causes of myelopathy. Neurology 90:12, 2018.

Kühl JS et al: Long-term outcomes of allogeneic haematopoietic stem

cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain 140:953, 2017.

Levi AD, Schwab JM: A critical reappraisal of corticospinal tract

somatotopy and its role in traumatic cervical spinal cord syndromes.

J Neurosurg Spine 12:1, 2021.

Ozpinar A et al: Epidemiology, clinical presentation, diagnostic evaluation, and prognosis of spinal arteriovenous malformations. Handb

Clin Neurol 143:145, 2017.

Parks NE: Metabolic and toxic myelopathies. Continuum (Minneap

Minn) 27:143, 2021.

Patchell RA et al: Direct decompressive surgical resection in the

treatment of spinal cord compression caused by metastatic cancer:

A randomised trial. Lancet 366:643, 2005.

Robertson CE et al: Recovery after spinal cord infarcts: Long-term

outcome in 115 patients. Neurology 78:114, 2012.

Ropper AE, Ropper AH: Acute spinal cord compression. N Engl J Med

376:1358, 2017.

Ruet A et al: Predictive factors for multiple sclerosis in patients with

clinically isolated spinal cord syndrome. Mult Scler 17:312, 2011.

Yáñez ML et al: Diagnosis and treatment of epidural metastases.

Cancer 123:1106, 2017.

Zalewski NL, Flanagan EP: Autoimmune and paraneoplastic

myelopathies. Semin Neurol 38:278, 2018.

Zalewski NL et al: Characteristics of spontaneous spinal cord infarction and proposed diagnostic criteria. JAMA Neurol 76:56, 2019.

TABLE 442-4 Expected Neurologic Function Following Complete Cord Lesions

LEVEL SELF-CARE TRANSFERS MAXIMUM MOBILITY

High quadriplegia (C1–C4) Dependent on others; requires respiratory

support

Dependent on others Motorized wheelchair

Low quadriplegia (C5–C8) Partially independent with adaptive

equipment

May be dependent or independent May use manual wheelchair, drive an

automobile with adaptive equipment

Paraplegia (below T1) Independent Independent Ambulates short distances with aids

Source: Adapted from JF Ditunno, CS Formal: Chronic spinal cord injury. N Engl J Med 330:550, 1994.

3456 PART 13 Neurologic Disorders

■ INTRODUCTION

Traumatic brain injury (TBI) represents a significant global public health

problem. In the United States, estimates of the frequency of TBI range

between 2.5 and 4 million cases per year, depending on the study and

methods used to define and include cases. Age-specific rates show a

bimodal distribution, with highest risk in younger individuals and

older adults. The most common mechanism of injury in the young is

motor vehicle accidents and is more common in men, whereas in older

adults, falls are the major cause of injury and are more likely to occur

in women.

TBI imposes substantial demands on health care systems. Worldwide, at least 10 million TBIs are serious enough to result in death or

hospitalization, producing a global economic burden of $400 billion

annually. In the United States, the estimated annual cost is >$76 billion.

Due to advances in medical care and other factors, more people are

surviving TBI than ever before. Brain injury accounts for more lost

productivity at work among Americans than any other form of injury.

An estimated 5.3 million Americans are living with significant disabilities resulting from TBI that complicate their return to a full and productive life. Increased media attention to military and sports-related

TBI has highlighted the growing concern that injuries that were previously dismissed can have lifelong consequences for some individuals.

Head injuries are so common that almost all physicians will be

called upon to provide some aspect of immediate care or to see

patients who are suffering from various sequelae. Patients and their

families initially need education regarding the natural history of TBI

along with treatment of acute symptoms such as headache. Continued

follow-up is important to ensure that the sequelae experienced by

some patients—such as postconcussive disorder (PCD), depression,

or sleep disorder—are identified and treated appropriately. Effective

management of TBI and its consequences often requires a coordinated

multidisciplinary care team.

■ DEFINITION AND CLASSIFICATION

TBI is commonly defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force, and characterized

by the following: (1) any period of loss or decreased level of consciousness

(LOC), (2) any loss of memory for events immediately before (retrograde)

or after (posttraumatic) the injury, (3) any neurologic deficits, and/or (4)

any alteration in mental state at the time of injury.

Evidence of TBI can include visual, neuroradiologic, or laboratory

confirmation of damage to the brain, but TBI is more often diagnosed

on the basis of acute clinical criteria. In addition to standard CT imaging, structural MRI and functional imaging (resting-state functional

MRI) techniques show increasing sensitivity, and it is likely that sensitive blood-based biomarkers will play an increasingly important role in

the diagnosis and treatment of these patients (described below).

MECHANISMS OF TBI Common mechanisms of TBI include the head

being struck by an object, the head striking an object, the brain

undergoing an acceleration/deceleration movement, a foreign body

penetrating the brain, or forces generated from events such as a blast

or explosion. Motor vehicle crashes have historically been cited as the

most common cause of TBI. All forms of transportation, however,

are common causes of TBI, including motorcycle crashes, bicycle

accidents, skateboarding, and pedestrian injuries. The other leading

causes of TBI are falls, assaults, and sports, with varied frequency

across the lifespan. Certainly, there has been an increased focus on the

high frequency of mild TBI (mTBI), often referred to as concussion,

encountered by athletes participating in contact and collision sports

443

at all competitive levels, as well as the potential short-term effects and

long-term risks associated with sport-related concussion.

CLASSIFICATION OF TBI SEVERITY Numerous systems have been developed over the years to define and classify TBI severity along a continuum from mild to moderate to severe. These systems are usually

most applicable to closed head injuries. In nearly all classification

systems, TBI severity is graded based on acute injury characteristics

rather than postacute injury status, as other factors can intervene

to influence functional outcome. This can be problematic, as some

patients with severe TBI will have a full recovery and some with mild

TBI will be left with lifetime disability. Historically, the presence

and duration of unconsciousness and amnesia have been the main

points of distinction along the gradient of TBI severity. Current TBI

classification systems remain symptom-based and do not incorporate patho-anatomical or molecular features, such as CT findings and

blood-based biomarkers.

The Glasgow Coma Scale (GCS) is the most recognized and widely

used method for grading TBI severity. The GCS provides a practical

indicator of gross neurologic status by assessing motor function, verbal

responses, and the patient’s ability to open his or her eyes voluntarily or

in response to external commands and stimuli. The grading is applied

to the best response that can be elicited from the patient at the time of

assessment, preferably before any paralyzing or sedating medication

is administered or the patient is intubated, as these interventions confound interpretation of the score. The GCS assessment produces scores

ranging from 3 to 15 (Table 443-1).

Upon the 40th anniversary of the GCS in 2014, the wording for

responses was revised, and recommendations were made to improve its

utility. Importantly, individual patients are best described by the three

components of the coma scale (eye, verbal, motor, e.g., E3V4M6); the

derived total coma score (e.g., 13) is less informative and should only

be used to characterize groups of patients.

Several injury-classification systems have been developed to go

beyond GCS score or acute injury characteristics and incorporate chief

signs and symptoms in defining mTBI. The use of multiple severity

indicators is intended to improve sensitivity in the detection of mTBI

(GCS 13–15), while also taking into consideration traditional acute

injury characteristics that have been presumed to predict outcome following mild and moderate brain injury. Loss of consciousness (LOC)

and posttraumatic amnesia (PTA) remain the most common injury

characteristics referenced in these classification systems. In the case

of moderate (GCS 9–12) and severe (GCS 3–8) TBI, GCS score and

the duration of LOC and PTA can be robust predictors of long-term

outcome and morbidity. In cases of mTBI, however, while PTA and

LOC are important indicators of acute injury, they are less predictive

of eventual recovery time and outcome.

Concussion and Other

Traumatic Brain Injuries

Geoffrey T. Manley, Benjamin L. Brett,

Michael McCrea

TABLE 443-1 Glasgow Coma Scale

EYE OPENING (E) VERBAL RESPONSE (V)

Spontaneous 4 Oriented 5

To speech 3 Confused 4

To pressure 2 Words 3

None 1 Sounds 2

None 1

Best Motor Response (M)

Obeying commands 6

Localizing 5

Normal flexion 4

Abnormal flexion 3

Extension 2

None 1

Note: Revised GCS (2014).

Source: Reproduced with permission from G Teasdale et al: The Glasgow Coma

Scale at 40 years: Standing the test of time. Lancet Neurol 13:844, 2014.

3457Concussion and Other Traumatic Brain Injuries CHAPTER 443

■ TBI TYPES AND PATHOLOGIES

MILD TBI (CONCUSSION) It is estimated that 70–90% of all treated TBIs

are mild in severity based on traditional case definitions and acute

injury characteristics, with most reported estimates in the order of

85%. The published figures likely underrepresent the true incidence of

mTBI because of variable case definitions and heterogeneous methods.

Moreover, because a subgroup of individuals with milder brain injuries

does not seek medical attention, epidemiologic studies that depend on

hospital-based data also underestimate the true incidence.

The term concussion, while popular, is vague and is not based on

widely accepted objective criteria, resulting in multiple definitions from

various groups. There has been debate as to whether concussion is part

of the TBI spectrum or a separate entity. In 2017, the Concussion in

Sports Group issued a consensus statement that “concussion is a traumatic brain injury” (McCrory et al, 2017). By firmly placing concussion

in the spectrum of TBI, the underlying pathophysiologic processes

common to all TBI presentations can now be considered together.

CT imaging is often normal in this population. However, emerging

evidence indicates that 3-tesla (3T) MRI scans can identify pathology

consistent with acute brain injury such as contusion and microhemorrhage. When patients with mTBI have CT and/or MRI abnormalities,

they are often referred to as complicated mTBI and are more likely to

have an unfavorable outcome.

■ SKULL FRACTURE, EXTRA-AXIAL HEMATOMA,

CONTUSION, AND AXONAL INJURY

Skull Fracture A blow to the skull that exceeds the elastic tolerance

of the bone causes a fracture. Intracranial lesions accompany roughly

two-thirds of skull fractures, and the presence of a fracture increases

many-fold the chances of an underlying subdural or epidural hematoma.

Consequently, fractures are primarily markers of the site and severity of

injury. If the underlying arachnoid membrane has been torn, fractures

also provide potential pathways for entry of bacteria to the cerebrospinal

fluid (CSF) with a risk of meningitis and for leakage of CSF outward

through the dura. If there is leakage of CSF, severe orthostatic headache

results from lowered pressure in the spinal fluid compartment.

Most fractures are linear and extend from the point of impact

toward the base of the skull. Basilar skull fractures are often extensions

of adjacent linear fractures over the convexity of the skull but may

occur independently owing to stresses on the floor of the middle cranial fossa or occiput. Basilar fractures are usually parallel to the petrous

bone or along the sphenoid bone and directed toward the sella turcica

and ethmoidal groove. Although most basilar fractures are uncomplicated, they can cause CSF leakage, pneumocephalus, and delayed

cavernous-carotid fistulas. Hemotympanum (blood behind the tympanic membrane), ecchymosis over the mastoid process (Battle sign),

and periorbital ecchymosis (“raccoon sign”) are clinical signs associated

with basilar fractures.

■ EPIDURAL AND SUBDURAL HEMATOMAS

Hemorrhages between the dura and skull (epidural) or beneath the

dura (subdural) have characteristic clinical and imaging features. They

are sometimes associated with underlying brain contusions and other

injuries, often making it difficult to determine the relative contribution

of each component to the clinical state. The mass effect of raised intracranial pressure (ICP) caused by these hematomas can be life threatening, making it imperative to identify them rapidly by CT or MRI scan

and to surgically remove them when appropriate.

Epidural Hematoma (Fig. 443-1) These highly dangerous lesions

usually arise from an injury to a meningeal arterial vessel and evolve

rapidly. They are often accompanied by a “lucid interval” of several

minutes to hours prior to neurologic deterioration. They occur in up

to 10% of cases of severe head injury, but are less often associated with

underlying cortical damage compared to subdural hematomas. Rapid

surgical evacuation and ligation or cautery of the damaged vessel,

usually the middle meningeal artery that has been lacerated by an

overlying skull fracture, is indicated. If recognized and treated rapidly,

patients often have a favorable outcome.

Acute Subdural Hematoma (Fig. 443-2) Direct cranial trauma

may be minor and is not always required for acute subdural hemorrhage

to occur, especially in the elderly and those taking anticoagulant medications. Acceleration forces alone, as from whiplash, are sometimes sufficient to produce subdural hematoma. Up to one-third of patients have

a lucid interval lasting minutes to hours before coma supervenes, but

most are drowsy or comatose from the moment of injury. A unilateral

headache and slightly enlarged pupil on the side of the hematoma are

frequently, but not invariably, present. Small subdural hematomas may

be asymptomatic and usually do not require surgical evacuation if they

do not enlarge. Stupor or coma, hemiparesis, and unilateral pupillary

enlargement are signs of larger hematomas. The bleeding that causes

larger subdural hematomas is primarily venous in origin, although

arterial bleeding sites are sometimes found at operation, and a few large

hematomas have a purely arterial origin. In an acutely deteriorating

patient, an emergency craniotomy is required. In contrast to epidural

hematomas, there is significant morbidity and mortality associated

with acute subdural hematomas that require surgery.

Chronic Subdural Hematoma A subacutely evolving syndrome

due to subdural hematoma occurs days or weeks after injury with

drowsiness, headache, confusion, or mild hemiparesis, usually in the

elderly with age-related atrophy and often after only minor or unnoticed

trauma. On imaging studies, chronic subdural hematomas appear as

crescentic clots over the convexity of one or both hemispheres, most

FIGURE 443-1 Acute epidural hematoma. The tightly attached dura is stripped from

the inner table of the skull, producing a characteristic lenticular-shaped hemorrhage

on noncontrast CT scan. Epidural hematomas are usually caused by tearing of the

middle meningeal artery following fracture of the temporal bone.

FIGURE 443-2 Acute subdural hematoma. Noncontrast CT scan reveals a

hyperdense clot that has an irregular border with the brain and causes more

horizontal displacement (mass effect) than might be expected from its thickness.

The disproportionate mass effect is the result of the large rostral-caudal extent of

these hematomas. Compare to Fig. 443-1.

3458 PART 13 Neurologic Disorders

commonly in the frontotemporal region (Fig. 443-3). A history of

trauma may or may not be elicited in relation to chronic subdural hematoma; the injury may have been trivial and forgotten, particularly in

the elderly and those with clotting disorders. Headache is common but

not invariable. Additional features that may appear weeks later include

slowed thinking, vague change in personality, seizure, or a mild hemiparesis. The headache typically fluctuates in severity, sometimes with

changes in head position. Drowsiness, inattentiveness, and incoherence

of thought are generally more prominent than focal signs such as hemiparesis. Rarely, chronic hematomas cause brief episodes of hemiparesis

or aphasia that are indistinguishable from transient ischemic attacks.

CT without contrast initially shows a low-density mass over the

convexity of the hemisphere. Between 2–6 weeks after the initial bleeding, the clot becomes isodense compared to adjacent brain and may be

inapparent. Many subdural hematomas that are several weeks in age

contain areas of blood and intermixed serous fluid. Infusion of contrast

material demonstrates enhancement of the vascular fibrous capsule

surrounding the collection. MRI reliably identifies both subacute and

chronic hematomas.

Clinical observation coupled with serial imaging is a reasonable

approach to patients with few symptoms and small chronic subdural

collections that do not cause mass effect. Treatment with surgical evacuation through burr holes is usually successful, if a cranial drain is used

postoperatively. The fibrous membranes that grow from the dura and

encapsulate the collection may require removal with a craniotomy to

prevent recurrent fluid accumulation.

■ TRAUMATIC SUBARACHNOID HEMORRHAGE

Subarachnoid hemorrhage (SAH) is common in TBI. Rupture of small

cortical arteries or veins can cause bleeding into the subarachnoid

space. Traumatic SAH is often seen in the sulci and is frequently the

only radiographic finding on CT following mild TBI. SAH occurs

diffusely after severe TBI and confers an increase in mortality. In mild

TBI, SAH provides an objective imaging biomarker for TBI, and in

some patients is associated with unfavorable outcomes.

Contusion (Fig. 443-4) A surface bruise of the brain, or contusion,

consists of varying degrees of petechial hemorrhage, edema, and tissue

destruction. Contusions and deeper hemorrhages result from mechanical forces that displace and compress the hemispheres forcefully and

by deceleration of the brain against the inner skull, either under a point

of impact (coup lesion) or, as the brain swings back, in the antipolar

area (contrecoup lesion). Trauma sufficient to cause prolonged unconsciousness usually produces some degree of contusion. Blunt deceleration impact, as occurs against an automobile dashboard or from falling

forward onto a hard surface, causes contusions on the orbital surfaces

of the frontal lobes and the anterior and basal portions of the temporal

lobes. With lateral forces, as from impact on an automobile door frame,

contusions are situated on the lateral convexity of the hemisphere. The

clinical signs of contusion are determined by the location and size of

the lesion; often, there are no focal abnormalities with a routine neurologic exam, but these injured regions are later the sites of gliotic scars

that may produce seizures. A hemiparesis or gaze preference is fairly

typical of moderately sized contusions. Large bilateral contusions produce stupor with extensor posturing, while those limited to the frontal

lobes cause a taciturn state. Contusions in the temporal lobe may cause

delirium or an aggressive, combative syndrome. Torsional or shearing

forces within the brain can cause hemorrhages of the basal ganglia and

other deep regions. Large contusions and hemorrhages after minor

trauma should raise concerns for coagulopathy due to an underlying

disease or more commonly anticoagulant therapy.

Acute contusions are easily visible on CT and MRI scans, appearing

as inhomogeneous hyperdensities on CT and as hyperintensities on T2

and fluid-attenuated inversion recovery (FLAIR) MRI sequences; there

is usually surrounding localized brain edema and some subarachnoid

bleeding. Blood in the CSF due to trauma may provoke a mild inflammatory reaction. Over a few days, contusions acquire a surrounding contrast

enhancement and edema that may be mistaken for tumor or abscess.

Axonal Injury (Fig. 443-5) Traumatic axonal injury (TAI) is

one of the most common injuries after TBI. There is disruption, or

shearing, of axons at the time of impact and this is associated with

FIGURE 443-3 CT scan of chronic bilateral subdural hematomas of different

ages. The collections began as acute hematomas and have become hypodense in

comparison to the adjacent brain after a period during which they were isodense

and difficult to appreciate. Some areas of resolving blood are contained on the more

recently formed collection on the left (arrows).

FIGURE 443-4 Traumatic cerebral contusion. Noncontrast CT scan demonstrating a

hyperdense hemorrhagic region in the anterior temporal lobe.

FIGURE 443-5 Multiple small areas of hemorrhage and tissue disruption in the

white matter of the frontal lobes on noncontrast CT scan. These appear to reflect

an extreme type of the diffuse axonal shearing lesions that occur with closed head

injury.

3459Concussion and Other Traumatic Brain Injuries CHAPTER 443

microhemorrhages. It occurs following high-speed deceleration injuries, such as motor vehicle collisions (Johnson et al, 2013). The presence of ≥4 areas of TAI is called diffuse axonal injury (DAI), and when

widespread, has been proposed to explain persistent coma and the vegetative state after TBI (Chap. 28). Only severe TAI lesions that contain

substantial blood are visualized by CT, usually in the corpus callosum

and centrum semiovale. More commonly, the CT will be negative for

TAI, but subsequent MRI, particularly gradient-echo or susceptibility

-weighted imaging, will show hemosiderin deposits reflective of microhemorrhages in addition to the axonal damage on diffusion sequences.

Traditionally, TAI and DAI have been considered as sequelae much

more likely to result from moderate and severe injuries. Accumulating

evidence has demonstrated that diffuse white matter abnormalities

purportedly reflective of axonal injury, such as changes in microstructure and neurite density, are quite common in mild TBI as well. The

degree of these changes correlates with metrics of injury severity (e.g.,

symptom burden) and recovery duration.

■ CRANIAL NERVE INJURIES

The cranial nerves most often injured with TBI are the olfactory, optic, oculomotor, and trochlear nerves; the first and second

branches of the trigeminal nerve; and the facial and auditory nerves.

Anosmia and an apparent loss of taste (actually a loss of perception

of aromatic flavors, with retained elementary taste perception) occur

in ~10% of persons with serious head injuries, particularly from falls

on the back of the head. This is the result of displacement of the brain

and shearing of the fine olfactory nerve filaments that course through

the cribriform bone. At least partial recovery of olfactory and gustatory function is expected, but if bilateral anosmia persists for several

months, the prognosis is poor. Partial optic nerve injuries from closed

trauma result in blurring of vision, central or paracentral scotomas,

or sector defects. Direct orbital injury may cause short-lived blurred

vision for close objects due to reversible iridoplegia. Diplopia limited

to downward gaze and corrected when the head is tilted away from

the side of the affected eye indicates trochlear (fourth nerve) nerve

damage. It occurs frequently as an isolated problem after minor head

injury or may develop for unknown reasons after a delay of several

days. Facial nerve injury caused by a basilar fracture is present immediately in up to 3% of severe injuries; it may also be delayed for

5–7 days. Fractures through the petrous bone, particularly the less

common transverse type, are liable to produce facial palsy. Delayed

facial palsy occurring up to a week after injury, the mechanism of

which is unknown, has a good prognosis. Injury to the eighth cranial

nerve from a fracture of the petrous bone causes loss of hearing, vertigo, and nystagmus immediately after injury. Deafness from eighth

nerve injury is rare and must be distinguished from blood in the middle ear or disruption of the middle ear ossicles. Dizziness, tinnitus,

and high-tone hearing loss occur from cochlear concussion.

■ SEIZURES

Convulsions are surprisingly uncommon immediately after TBI, but a

brief period of tonic extensor posturing or a few clonic movements of

the limbs just after the moment of impact can occur. However, the cortical scars that evolve from contusions are highly epileptogenic and may

later manifest as seizures, even after many months or years (Chap. 425).

The severity of injury roughly determines the risk of future seizures.

It has been estimated that 17% of individuals with brain contusion,

subdural hematoma, or prolonged LOC will develop a seizure disorder

and that this risk extends for an indefinite period of time, whereas the

risk is ≤2% after mild injury. The majority of convulsions in the latter

group occur within 5 years of injury but may be delayed for decades.

Penetrating injuries have a much higher rate of subsequent epilepsy.

CLINICAL SYNDROMES AND TREATMENT

OF HEAD INJURY

■ CONCUSSION/MILD TBI

The patient who has briefly lost consciousness or been stunned after

a minor head injury usually becomes fully alert and attentive within

minutes but may complain of headache, dizziness, faintness, nausea, a

single episode of emesis, difficulty with concentration, a brief amnestic

period, or slight blurring of vision. This typical concussion syndrome

has a good prognosis with little risk of subsequent deterioration.

Children are particularly prone to drowsiness, vomiting, and irritability, symptoms that are sometimes delayed for several hours after

apparently minor injuries. Vasovagal syncope that follows injury may

cause undue concern. Generalized or frontal headache is common in

the following days. It may be migrainous (throbbing and hemicranial)

in nature or aching and bilateral. After several hours of observation,

patients with minor injury may be accompanied home and observed

for a day by a family member or friend, with written instructions to

return if symptoms worsen.

Persistent severe headache and repeated vomiting in the context

of normal alertness and no focal neurologic signs is usually benign,

but CT should be obtained and a longer period of observation is

appropriate. The decision to perform imaging tests also depends on

clinical signs that indicate that the impact was severe (e.g., persistent

confusion, repeated vomiting, palpable skull fracture); the presence

of other serious bodily injuries, an underlying coagulopathy, or age

>65 years; and on the degree of surveillance that can be anticipated after discharge. Guidelines have also indicated that older age

(>65 years), two or more episodes of vomiting, >30 min of retrograde

or persistent anterograde amnesia, seizure, and concurrent drug or

alcohol intoxication are sensitive (but not specific) indicators of intracranial hemorrhage that justify CT scanning.

Though not incorporated into conventional clinical practice guidelines, growing evidence suggests that MRI improves sensitivity for

detection of small intracranial hemorrhages and other lesions in

mild TBI patients, particular among those with negative findings

on CT. Specifically, intracranial abnormalities are fairly common

on MRI (27%) in CT-negative patients. Further, acute MRI findings

have prognostic utility in predicting recovery and outcome after mTBI/

concussion (e.g., risk of functional impairment, time to return to activity).

Blood-based (serum and plasma) biomarkers of astrocyte damage/

astrogliosis (glial fibrillary acidic protein [GFAP]) and neuronal injury

(ubiquitin carboxy-terminal hydrolase L1 [UCHL1]) also hold promise

in improving detection and outcome prediction across the full spectrum of TBI. With development of new rapid assay systems, these can

now be used for real-time point-of-care assessment; GFAP in particular

has high discriminant ability to detect intracranial abnormalities, as

well as potential to differentiate CT+, CT–/MRI+, and CT–/MRI–

patients. Similar to MRI, emerging biomarkers appear to have not

only diagnostic but also prognostic utility in predicting the trajectory

of recovery and functional impairments weeks and months after TBI.

■ SPORT-RELATED CONCUSSION

Based on its reported prevalence, acute effects, and fears over potential long-term neurologic consequences, sport-related concussion has

become the focus of increasing concern from clinicians, researchers,

sporting organizations, and athletes themselves. Concussion is a frequent injury in contact and collision sports (e.g., football, hockey, wrestling) at all levels of participation, including youth sports. Head injury

associated with sport and recreational activity accounts for 45% of

TBI-related emergency department visits in children age 17 years and

under. Between 1997 to 2007, emergency department visits for 8- to

13-year-old children affected by concussion in organized team sports

doubled, and increased by >200% in the 14- to 19-year-old group.

Over the last decade, data from the Centers for Disease Control and

Prevention indicate that this trend has reversed, with a 27% decrease

in emergency department visits for sport- and recreation-related TBI

in the United States between 2012 and 2018. Given that national and

state surveillance systems continue to report increased sport-related

concussion rates over the same time period, it could be inferred that

diagnosis and management of sport-related concussion outside of the

emergency department has increased.

The natural history of clinical recovery following sport-related concussion has been a subject of substantial ongoing research. In general,

the findings on acute recovery are favorable. A 2003 report was the first

to chart the continuous time course of acute recovery within several

3460 PART 13 Neurologic Disorders

days after concussion, indicating that >90% of athletes reported symptom recovery within 1 week. Several other prospective studies have

since demonstrated that the overwhelming majority of athletes achieve

a complete recovery in symptoms, cognitive functioning, postural

stability, and other functional impairments over a period of 1–3 weeks

following concussion.

In recent years, a paradigm shift toward a more rapid return to

activity and a focus on rehabilitation has occurred. Specifically, while

experts agree that initial rest post-injury is beneficial for recovery,

extended inactivity beyond 5 days can be detrimental and increase risk

for protracted recovery. Rather, active rehabilitation involving supervised subthreshold exercise has been shown to improve duration of

symptoms and decrease risk of protracted recovery.

There are many anecdotal reports, however, of athletes who remain

symptomatic or impaired on functional testing well beyond the window of recovery commonly reported in group studies. The greatest

challenge arguably still facing sport medicine clinicians and public

health experts is how to most effectively manage and reduce risk in this

subset of athletes who do not follow the “typical” course of recovery.

The precise frequency of athletes who do not follow the typical course

of rapid, spontaneous recovery and instead exhibit prolonged postconcussive symptoms or other functional impairments after concussion

remains unclear. Postinjury symptom burden is the most robust predictor of recovery and risk of prolonged symptoms. Preinjury mental

health diagnosis and history of prior concussion are two factors that

have been consistently identified as being associated with potential for

prolonged recovery as well.

Following acute concussion, multimodal advanced neuroimaging

has demonstrated a variety of changes, including decreased cerebral

blood flow, increased global and local functional connectivity, and

alterations in white matter microstructure reflecting axonal organization. In general, these metrics correlate with measures of injury

severity, and resolution of these changes tends to parallel clinical

recovery. However, a number of studies have shown that slight changes

on advanced multimodal imaging can persist even after symptoms

have fully resolved, supporting the concept that the “tail” of neurobiologic recovery may extend beyond the time course of apparent clinical

recovery.

In the current absence of adequate data, a commonsense approach

to athletic concussion has been to remove the individual from play

immediately and avoid contact sports for at least several days after a

mild injury, and for a longer period if there are more severe injuries

or if there are protracted neurologic symptoms such as headache and

difficulty concentrating. No individual should return to play unless

all concussion-related symptoms have resolved and an assessment

has been made by a health care professional who has experience with

treatment of concussion. Validated symptom inventories, such as the

Rivermead Post-Concussion Symptom Questionnaire (Table 443-2),

have been developed to aid clinicians with recording and quantifying

the diverse range of physical, cognitive, and behavioral symptoms

that can occur following concussion. In addition to characterizing the

constellation of acute symptoms and their severity, symptom inventories can be beneficial to track the course and resolution of symptoms

through recovery. Differentiating concussion-related symptoms from

factors that may be also influencing endorsement (e.g., preinjury mood

difficulties) is an important component of managing recovery from

sport-related concussion. Once cleared, the individual can then begin a

graduated program of increasing activity. Younger athletes are particularly likely to experience protracted concussive symptoms, and a slower

return to play in this age group may be reasonable. These guidelines

are designed in part to avoid a perpetuation of symptoms but also to

prevent the rare second-impact syndrome, in which diffuse and fatal

cerebral swelling follows a second minor head injury.

■ POSTCONCUSSIVE STATES

The postconcussion syndrome (PCS) refers to a state following mild

TBI consisting of combinations of fatigue, dizziness, headache, and

difficulty in concentration. Management is difficult and generally

requires the identification and management of the specific problem or

problems that are most troubling to the individual. A clear explanation

and education around the symptoms that may follow concussion has

been shown to reduce subsequent complaints. Care is taken to avoid

prolonged use of drugs that produce dependence. Headache may initially be treated with acetaminophen and small doses of amitriptyline.

Vestibular exercises (Chap. 22) and small doses of vestibular suppressants such as promethazine (Phenergan) may be helpful when dizziness

is the main problem. Patients, who after mild or moderate injury have

difficulty with memory or with complex cognitive tasks at work, may

be reassured to know that these problems usually improve over several

months, and a reduced workload or other accommodations may be

prescribed in the interim.

For the vast majority of individuals with mTBI, the symptoms of

PCS subside and resolve within a few weeks of injury. For a subset of

individuals with mTBI, however, complaints of postconcussion symptoms persist beyond the expectation derived from TBI severity markers. The term postconcussion disorders (PCDs) has been proposed for

diagnostic use and to improve characterization of specific symptoms

or types of sequelae following mTBI. These include neurologic, cognitive, behavioral, or somatic complaints that continue beyond the acute

and subacute periods, becoming chronic and often operationalized as

persisting beyond 3 months. Although the overall risk of developing

PCD following mTBI is low, the frequency of mTBI patients who

meet criteria for a diagnosis of PCD and present in a clinical setting is

believed to be higher.

mTBI patients with PCD frequently present to the outpatient clinics of primary care physicians, physiatrists, or neurologists seeking

relief for lingering PCD-related symptoms. While some patients will

have already received an initial medical workup to rule out a more

serious brain injury during the acute phase, many patients will have

had no prior contact with health care specialists. A medical workup

ordered in the outpatient setting for PCD-related complaints is typically unremarkable for any identifiable neurologic cause to account

for the persisting symptoms reported by the patient. The development

of uniform decision trees or “standard of care” treatment regimens for

PCD-related symptoms has been limited by the diversity of symptoms

that patients experience, even within mTBI subgroups that have sustained very similar injury patterns. While some patients experience

somatic symptoms, others complain of subjective cognitive or behavioral changes. Symptom inventories (Table 443-2) can be helpful in

documenting the broad range of these symptoms and serve as a metric

for improvement following symptom-based treatment.

Active rehabilitation for the treatment of PCD involving subthreshold exercise has increased in popularity over recent years and has

gained empirical support for its effectiveness as a useful intervention

for protracted recovery.

PCD is not a unidimensional condition but rather an outcome

influenced by diverse cognitive, emotional, medical, psychosocial, and

motivational factors. Because of this complexity, treatments targeting

TABLE 443-2 Review of Concussion Symptoms

PHYSICAL COGNITIVE BEHAVIORAL

Headaches Forgetfulness or poor

memory

Being irritable, easily

angered

Dizziness Poor concentration Feeling depressed or

tearful

Nausea and/or vomiting Taking longer to think Feeling frustrated or

impatient

Noise sensitivity Restlessness

Sleep disturbance

Fatigue

Blurred vision

Light sensitivity

Double vision

Note: Items were adapted from the Rivermead Post-Concussion Symptom

Questionnaire. Each item is rated on a 5-point Likert scale (0–4), as follows: 0 = Not

experienced at all; 1 = No more of a problem now than preinjury; 2 = A mild problem;

3 = A moderate problem; 4 = A severe problem. Total scores can range from 0–64.

3461Concussion and Other Traumatic Brain Injuries CHAPTER 443

persistent and refractory PCD-related symptoms should be tailored to

the needs and expectations of the individual patient, with referrals to

specialists as needed for assistance with management of headache, neck

and back pain, dizziness and vertigo, and other symptoms reported

within the context of PCD. A comprehensive review of concussion- and

PCD-related symptoms presented in Table 443-2 allows for development of an individualized approach that leverages currently available

treatment for those sequelae that are most bothersome to the patient

(e.g., vestibular rehabilitation therapy for vertigo, melatonin for sleep

disturbance). Patients are frequently referred to behavioral health providers such as neuropsychologists, rehabilitation psychologists, health

psychologists, and/or psychiatrists for a variety of reasons, but particularly when they are experiencing cognitive, emotional, or behavioral

changes that accompany PCD. Patients with mood disorders (e.g.,

depression), anxiety disorders (e.g., posttraumatic stress disorder), or

adjustment reactions may benefit from psychiatric consultation for

appropriate medication trials or from time-limited psychotherapy such

as cognitive behavioral therapy.

Due to the complexity of presentation and varying diagnostic criteria, there are limited studies regarding overall prognosis of PCD. However, treatment of PCD-related symptoms targeted to the individual’s

specific difficulties can improve functional outcomes and patient-rated

quality of life. Further, collaborative care has been shown to improve

outcomes among patients experiencing persistent postconcussion

symptoms. These improved outcomes are likely due to a multidisciplinary team’s ability to simultaneously address the diverse set of symptoms

that can occur with PCD.

■ INJURY OF INTERMEDIATE SEVERITY

Patients who are not fully alert or have persistent confusion, behavioral changes, extreme dizziness, or focal neurologic signs such as

hemiparesis should be admitted to the hospital and undergo a cerebral

imaging study. A cerebral contusion or hematoma will usually be

found. Common syndromes include: (1) delirium with a disinclination

to be examined or moved, expletive speech, and resistance if disturbed

(anterior temporal lobe contusions); (2) a quiet, disinterested, slowed

mental state (abulia) alternating with irascibility (inferior frontal

and frontopolar contusions); (3) a focal deficit such as aphasia or mild

hemiparesis (due to subdural hematoma or convexity contusion or,

less often, carotid artery dissection); (4) confusion and inattention,

poor performance on simple mental tasks, and fluctuating orientation

(associated with several types of injuries, including those described

above, and with medial frontal contusions and interhemispheric

subdural hematoma); (5) repetitive vomiting, nystagmus, drowsiness,

and unsteadiness (labyrinthine concussion, but occasionally due to a

posterior fossa subdural hematoma or vertebral artery dissection); and

(6) diabetes insipidus (damage to the median eminence or pituitary

stalk). Injuries of this degree can be complicated by drug or alcohol

intoxication, and clinically inapparent cervical spine injury may be

present. Blast injuries are often accompanied by rupture of the tympanic membranes.

After surgical removal of hematomas, patients in this category

improve over weeks to months. During the first week, the state of

alertness, memory, and other cognitive functions often fluctuate, and

agitation and somnolence are common. Behavioral changes tend to

be worse at night, as with many other encephalopathies, and may be

treated with small doses of antipsychotic medications. Subtle abnormalities of attention, intellect, spontaneity, and memory return toward

normal weeks or months after the injury, sometimes abruptly. However, the full extent of recovery may not be realized for several years.

Persistent cognitive problems are discussed below.

■ SEVERE INJURY

Patients who are comatose from the moment of injury require immediate neurologic attention and resuscitation. After intubation, with

care taken to immobilize the cervical spine, the depth of coma, pupillary size and reactivity, limb movements, and Babinski responses are

assessed. As soon as vital functions permit and cervical spine x-rays

and a CT scan have been obtained, the patient should be transported

to a critical care unit. Hypoxia should be reversed, and normal saline

used as the resuscitation fluid in preference to albumin. The finding of

an epidural or subdural hematoma or large intracerebral hemorrhage

is usually an indication for prompt surgery and intracranial decompression in an otherwise salvageable patient. Measurement of ICP

with a ventricular catheter or fiberoptic device in order to guide treatment has been favored by many units but has not improved outcome.

Similarly, induced hypothermia has shown no benefit. Hyperosmolar

intravenous solutions are used in various regimens to limit intracranial

pressure. Prophylactic antiepileptic medications are recommended for

7 days and should be discontinued unless there are multiple seizures

postinjury. Management of raised ICP, a frequent feature of severe head

injury, is discussed in Chap. 307.

Despite the improvement in mortality for severe TBI over the past

few decades, a great deal of therapeutic nihilism persists in TBI. The

common use of a 6-month outcome for TBI clinical studies reinforces

this misconception. The recovery from severe TBI can take years. Furthermore, the ability to predict long-term outcome is limited and frequently incorrect. Best-practice guidelines recommend, in the absence

of brain death, that aggressive therapy be instituted for at least 72 h in

the acute injury period.

■ LONG-TERM OUTCOMES IN TBI

TBI (aggregated mild to severe) is associated with a 63–96% increased

risk of all-cause dementia. The degree of risk for dementia ranges along

the gradient of TBI severity (i.e., greatest risk among severe injuries).

To date, investigations have less reliably established mTBI as a robust

risk factor for dementia, likely due to methodologic heterogeneity

(e.g., use of different diagnostic criteria, exposure misclassification,

self-report vs. physician diagnoses of TBI or dementia). Though an

identified risk factor for all-cause dementia, pathophysiologic and

epidemiologic factors that underlie the association between TBI with

risk of specific neurodegenerative pathologies and dementia-subtypes

are not well understood. As a result, associations between TBI with

clinical syndromes (e.g., Alzheimer’s disease, Parkinson’s disease,

amyotrophic lateral sclerosis) or distinct neuropathologies (e.g., betaamyloid, Lewy bodies, transactive response DNA-binding protein 43)

have been inconsistently reported in the literature. In a large study

involving clinical and neuropathologic data from three pooled prospective studies of community-based cohorts, a significant relationship

was found between TBI with LOC >1 h and subsequent Parkinson’s

disease diagnosis, progression rate of parkinsonism, and Lewy body

accumulation at postmortem examination.

There is some evidence that repeated mTBI or sport-related concussions, particularly among boxing and professional American football

athletes, are associated with delayed and potentially progressive neurobehavioral changes. The brains of these patients display a characteristic

deposition of tau protein in neurons located in the superficial cortical

layers and perivascular regions, and particularly in the depths of sulci.

This pattern has been defined as the pathognomonic lesion of chronic

traumatic encephalopathy (CTE). A variety of neurodegenerative

pathologies are commonly found in the presence of CTE, adding to the

complexity of diagnosis. While staging criteria for this neuropathologic

entity have yet to be established, a consensus meeting to define the neuropathologic criteria for CTE proposed an algorithm assessing CTE as

“low” or “high” in severity. Overall, its contribution, if any, to late-life

dementia and parkinsonism in former athletes, soldiers, or others who

have sustained repeated concussive injuries is unknown.

Research criteria for the clinical diagnosis of CTE have been proposed, and include a range of cognitive and/or behavioral symptoms,

including executive dysfunction, depression, insomnia, and behavioral

dyscontrol. Multiple studies have suggested that these proposed criteria

lack specificity (i.e., they are frequent in other conditions and non-CTE

cases). As such, CTE remains a postmortem diagnosis. Advances in

positron emission tomography (PET) have allowed for in vivo investigation of tau deposition. Significant correlations between greater years

of football participation and greater standardized uptake value ratio

(SUVR) of 18F-flortaucipir (purportedly representative of tau deposition) in the bilateral superior frontal, bilateral medial temporal, and left