Catastrophic Neurologic Disorders in the Emergency Department , 2nd Edition

Chapter 18. Acute White Matter Diseases

Devastating white matter disorders are fulminant multiple sclerosis (MS), transverse myelitis, and disseminated encephalomyelitis. Even in academic institutions, they are sporadically seen. They are included in this book because it is important to diagnose and manage these disorders quickly.

Acute demyelination of the neuraxis may turn out catastrophic, and treatment in the acute phase remains problematic. Generally, rapid cures remain few and far between. However, aggressive immunosuppression or plasma exchange may shorten the relapse and, in certain disorders, resolve some or virtually all of its manifestations.

A related disorder, often with an acute onset, is acute leukoencephalopathy, occurring in a diverse group of patients. In this entity, demyelination or edema is part of a more global involvement of white matter structures. Toxicity from immunosuppressive and chemotherapeutic agents is commonly implicated or a hypertensive crisis may touch off white matter edema or demyelination. These disorders may resolve quickly after elimination of the trigger alone.

Acute Disseminated Encephalomyelitis

Acute Disseminated Encephalomyelitis (ADEM) is a dramatic monophasic illness resulting from an autoimmune response activated by a viral infection or vaccination. ADEM occurs more often in children and young adults, and most infections are mundane viral respiratory episodes. ADEM may also follow any well-defined illness (e.g., rubeola, varicella, mycoplasmal pneumonia,1,2 infectious mononucleosis, and hepatitis C3) or may occur without an identifiable antecedent event.

Even in the most severe fatal cases, use of polymerase chain reaction analysis to recover a virus (e.g., enterovirus, adenovirus, herpesvirus, and respiratory syncytial virus) from the brain during autopsy has not been successful (no virus has been isolated from the cerebrospinal fluid [CSF]). More recently, human herpesvirus 6 has been associated with ADEM.4 Neurologic manifestation occurs after a delay of 1–3 weeks but progresses rapidly to a maximum within days. Wide-spread involvement of the central nervous system may affect many eloquent areas of the brain and cord. White matter destruction involving the optic tract, brain stem, and spinal cord that resembles acute transverse myelitis is a classic finding if the disorder progresses. Pathologic features of ADEM include multifocal patchy perivenous demyelination.

Clinical Presentation

Patients or their consulted family members recall a flu-like illness with a variable combination of fever, aching joints, swollen lymph nodes, and fatigue. Some of these constitutional symptoms may still be present at onset.

Initially, headaches with transient focal neurologic signs may be prominent and fluctuating.

Neurologic findings further reflect acute myelin destruction and may consist of any degree of impairment of consciousness, with several prompts needed to alert patients to their surroundings. In others, ophthalmoplegia, cerebellar ataxia, and speech abnormality may evolve to muteness. Fever, loss of consciousness, and meningism, if present, are more common in patients with a single event.5

Spinal cord involvement may be the first presenting symptom or may quickly merge into a more diffuse or multifocal neurologic symptom complex. Progressive quadriparesis may result in early inability to walk, but level of consciousness should also become involved at this time.

Progression is within days, but a clinical course with up to 2 months of gradual, protracted change has been documented. ADEM can be mistaken for central nervous system lymphoma, vasculitis, viral encephalitis, and manifestations of flaring up rheumatologic disorders, some of which have yet to be diagnosed (Table 18.1).

Interpretation of Diagnostic Tests

Computed Tomography and Magnetic Resonance Imaging

Computed tomographic (CT) and magnetic resonance imaging (MRI) findings are fairly typical but may be rather subtle in earlier stages. The typical appearance in ADEM is multiple discrete lesions in the cerebral white matter and rarely in periventricular areas, a location much more typical of fulminant MS. The lesions predominate in occipital-parietal white matter (Fig. 18.1A,B) but may involve the basal ganglia, thalamus, and brain stem.6,7 A single bout confined to the brain stem has been recorded.8 Symmetrical cerebellar white matter and basal ganglia involvement may differentiate it from MS.9,10 All of these abnormalities may hardly be detected by CT, and only some decreased attenuation in the white matter of the centrum semiovale is seen, even at the stage of prominent neurologic manifestations. MRI remains a crucial determinant for its diagnosis. Gadolinium enhancement is a reflection of the blood-brain barrier breakdown in the earlier stages of demyelination. Enhancement may appear in some lesions on MRI and not in others, suggesting different stages in demyelination.11,12 Enhancement may be marginal because of corticosteroid treatment, which reduces the blood-brain barrier permeability.13 If enhancement is found, abnormal signal intensity is more commonly found in the optic nerves (as opposed to unilateral optic neuritis in MS). Generally, these MRI features cannot be easily differentiated from those of MS nor has a more distinct histologic feature been identified in brain tissue specimens.

Table 18.1. Disorders Mimicking Acute Disseminated Encephalomyelitis

Acute viral encephalitis (arboviruses)
Herpes simplex encephalitis
Central nervous system vasculitis
Intravascular lymphoma
Progressive multifocal leukoencephalopathy
Neurosarcoidosis
Systemic lupus erythematosus
Sjögren's disease

Hemorrhagic changes (Fig. 18.1C,D) suggest an acute hemorrhagic leukoencephalitis (Weston Hurst disease); and this disorder, noted after similar triggering circumstances, may primarily be an aggressive variant of ADEM. Not infrequently, it presents with massive brain edema.14,15 Hyper-intense lesions on T2-weighted images, with ring-like solid enhancing lesions and perifocal edema, have been reported as well. Cortical involvement is compatible with the diagnosis, albeit less extensively distributed.

Cerebrospinal Fluid

CSF may show moderate pleocytosis (up to 200 cells/mm3). In ADEM, the CSF contains lymphocytes; in Weston Hurst disease, polymorphonuclear leukocytes are prominent.14 The pleocytosis is usually out of proportion to what is expected during a flare-up of MS. Oligoclonal bands can be found in up to 50% of cases5 and may disappear after treatment (oligoclonal bands commonly persist in MS).

First Priority in Management

High-dose methylprednisolone (1000 mg intravenously daily) remains the first therapy of choice. Excellent recovery has also been observed with plasma exchange, and failure to improve rapidly (arbitrarily defined as 1–2 days) with cortico-steroids should prompt its use. The exact number of plasma exchanges is unknown, although exchanges for up to 10 days (or until improvement) have been proposed.16,17,18 Alternatively, intravenous immunoglobulin, 0.4 g/kg for 5 days, can be used,19,20 again, typically in patients worsening while receiving methylprednisolone.21,22

Figure 18.1 A,B: Magnetic resonance imaging with coronal views of acute disseminated encephalomyelitis. C,D: Hemorrhagic leukoencephalitis (Weston Hurst).

Predictors of Outcome

Improved arousal can be rather rapid and is followed by improvement in diplopia, bulbar dysfunction, and, more gradually, ambulation. Residual symptoms may remain but are in a minority disabling. MRI findings should closely parallel clinical improvement. Full recovery after Weston Hurst disease has been described in several cases. One study suggested that one of three patients with AD EM develops MS within 3 years; this included patients with well-established triggers such as infection or vaccination.5 This report also emphasized that the diagnosis of AD EM as a monophasic demyelinating disorder becomes likely only if the patient has remained asymptomatic for at least 1 year.5

Triage

·     A brief period of observation in the intensive care unit and support with mechanical ventilation may be needed, but in pa-are soon able to protect their airway and ventilate normally.

·     Brain biopsy should be deferred until the effect of immunosuppressive therapy or plasma exchange has been evaluated.

Fulminant Multiple Sclerosis

Patients with clinically definitive or laboratory-supported MS may have very severe exacerbations. Progression into a devastating condition or death rarely is the first presentation. The designation fulminant in this condition is usually defined by symptoms and signs emerging in days rather than weeks and presupposes involvement of multiple areas in the cerebral white matter and often the brain stem. Demyelination, which leads to loss of ambulation from weakness or ataxia, may involve the bulbar function and respiratory control. A brain biopsy, usually performed to characterize the source of a new mass, shows fairly typical neuropathologic features of marked inflammatory perivascular infiltrates, extensive myelin breakdown that spares the nerve cell bodies and axis cylinders, and diffuse macrophage infiltration.

Clinical Presentation

Earlier descriptions of this fulminant variant emphasized an accelerated development of ataxia, hemiparesis, or paraparesis; blindness or progressive ophthalmoplegia; and notable bulbar involvement leading to dysphagia and aspiration. Brain stem involvement is a common feature in acute fulminant MS. Quadriparalysis and involvement of the lower cranial nerves with sparing of only the oculomotor nerves closely resemble a locked-in syndrome and often are linked to a fatal outcome.23,24

The most dramatic variant, one with high mortality, is the Marburg variant.25,26 Within days, progressive ophthalmoplegia, dysarthria, dysphagia, and blindness may develop and the patient becomes comatose. An uncal brain herniation pattern appears when a large inflammatory demyelinating tumefactive lesion shifts brain tissue.

Mechanical ventilation is often needed in patients whose condition deteriorates to coma and in patients with bulbar signs. Neurogenic pulmonary edema as a result of sympathetic disinhibition may accompany the fulminant form.27 In most patients, marked bulbar failure and inability to swallow secretions lead to aspiration pneumonitis, and upper cervical or spinal cord involvement impairs pulmonary mechanics.28

Interpretation of Diagnostic Tests

The diagnostic criteria of MS, including laboratory abnormalities, have been expertly outlined. A modification of the Poser criteria is shown in Box 18.1.29

Computed Tomography and Magnetic Resonance Imaging

MRI assists in the diagnosis, but findings are nonspecific. MRI suggests demyelination when lesions are hypointense or isointense on T1-weighted images, occasionally display hyperintense edges, and are small, irregular, or confluent. White matter lesions are invariably located in the pons, medulla, additional hemispheric areas involving the junctions of gray and white matter, and corpus callosum. Larger confluent areas in periventricular white matter can be seen as well.30,31 Ovoid lesions at right angles to the ventricular surface are characteristic (Fig. 18.2). Unilateral mass effect with developing edema may occur. Mass effect may be the most prominent CT scan manifestation (Fig. 18.3). Ringlike structures may appear, corresponding to layers of macrophages, which generate free radicals to produce this paramagnetic effect.32 However, magnetic resonance spectroscopy studies have found that these rings more than likely represent central edema in the core of the ring plaque.33

Box 18.1. Diagnostic Criteria for Multiple Sclerosis

Category

Subcategory

No. of Clinical Attacks

No. of Clinically Evident Lesions

Paraclinical Evidence*

CSF Oligoclonal

CDMS

A1

2

2

N/A

N/A

A2

2

1

and 1 (or more)

N/A

A3

1

1

2

N/A

LSDMS

B1

2

1

or 1 (or more)

+

B2

1

2

-

+

B3

1

1

and 1 (or more)

+

CDMS, clinically definite multiple sclerosis; CSF, cerebrospinal fluid: LSDMS, laboratory-supported definite multiple sclerosis; N/A. not applicable; +. present.
*Implies magnetic resonance imaging, evoked potentials, or CSF.
† A diagnosis of CDMS A3 requires paraclinical evidence for dissemination in time as well as space.
Source: Paty DW, Noseworthy JH, Ebers GC: Diagnosis of multiple sclerosis. In DW Paty, GC Ebers (eds). Multiple Sclerosis. Contemporary Neurology Series. Philadelphia: FA Davis, 1998. p. 48. By permission of Oxford University Press.

Evoked Potentials

Evoked potential studies may detect asymptomatic lesions.34,35 Pattern reversal visual evoked potential is sensitive for lesions in the optic nerve and chiasm, and findings are abnormal in 40%–60% of patients with early MS.31 The sensitivity in median nerve somatosensory evoked potentials is similar. Brain stem auditory evoked potentials are less sensitive and positive in only 20%–25% of patients with MS.34

Evoked potentials probably are most useful for providing supportive laboratory evidence of MS when additional diagnostic tests are abnormal.35

Figure 18.2 Fulminant multiple sclerosis with multiple periventricular white matter lesions and characteristic scattered lesions in the corpus callosum and brain stem.

Cerebrospinal Fluid

Cell count can vary from 10 to 50 lymphocytes/ mm3, with a mixture of monocytes, plasma cells, and macrophages. Total protein is mildly increased, and immunoglobulin G (IgG) is increased in 70% of clinically definite MS. Two or more oligoclonal bands in the gamma field may be detected in only 40% of patients with first presentation of MS. Intrathecal immunoglobulin in the CSF is a result of increased plasma cell synthesis and leakage from the brain through a defective blood-brain barrier. Oligoclonal bands in the CSF (at least two different and distinct bands) but not in the serum are typical for MS but can occur in 8% of patients with other neurologic diseases that may superficially mimic MS (viral meningoencephalitis, neurosyphilis, sarcoidosis, and fungal meningitis). The sensitivity of oligoclonal bands in CSF for MS is more than 90%.36

Figure 18.3 Marked mass effect and edema common in the Marburg variant of multiple sclerosis.

First Priority in Management

Intravenous administration of methylprednisolone, 1 g per day for 3–5 days, is followed by 60 mg of prednisone.37 The number of contrast-enhancing lesions is significantly reduced.38 Tapering of oral prednisone should be completed in 14 days. Overall prognosis is not affected by corticosteroids. Azathioprine, methotrexate, cyclophosphamide, and cyclosporine have no demonstrated benefit in acute progressive MS.

High doses of corticosteroids may not be sufficient to counter the fulminant attack, and evidence in patients with fulminant MS suggests that plasma exchange may be useful.39,40 Improvement begins within several days, reversing quadriplegia and dependence on a mechanical ventilator. Plasmapheresis has shown no effect in long-term outcome of progressive MS, but it may be beneficial in fulminant exacerbations by removing soluble factors involved in the process of demyelination. The number of plasma exchanges is unknown, but up to six exchanges every other day may be needed.39,40

Two forms of recombinant interferon-beta should be considered. These agents decrease clinical relapses by 30%, halve the number of severe relapses, and lengthen time to first relapse. They are administered subcutaneously (interferon-beta-1b, 8 million units every other day) or intramuscularly (interferon-beta-la, 6 million units weekly). The effects of a new agent, glatiramer acetate (20 mg subcutaneously daily), are similar.41 An evidence-based report on therapy in MS has been made available by the American Academy of Neurology, and some of the pertinent conclusions are summarized in Table 18.2. There is insufficient proof of effect and concern of more harm using sulfasalazine, mitoxantrone, cyclophosphamide, and cladribine.42

Predictors of Outcome

Fulminant MS is associated with a high probability of permanent disability and with a somewhat shortened life span, strongly dependent on the degree of disability. Unfavorable prognostic factors are age over 40, male gender, and extensive MRI abnormalities (increased T2 lesion load and number of active enhancing lesions). The relapse rate varies after a first major attack but decreases over time. After the first attack, approximately 25% of patients have a relapse within 1 year and 50% within 3 years. The extent of disability 5 years after the diagnosis strongly determines the future clinical course.29 Recovery may be protracted, lasting 3–4 weeks; and intercurrent infections may contribute to early mortality.

Triage

·     Early aspiration pneumonia, fever, or major oropharyngeal involvement justifies admission to an intensive care unit.

·     Placement of an intracranial pressure device is warranted in the Marburg variant of MS, to monitor clinical progression and treat increased intracranial pressure.

·     Neurosurgical consultation for craniotomy or biopsy may be needed to pathologically confirm the diagnosis.

Table 18.2. Therapy in Multiple Sclerosis (MS)

Drug/Procedure

Specific Effect

Effectiveness

Glucosteroids

Shorten acute attack

Established

Reduce attack rate of relapsing-remitting MS

Possible

Interferon-β

Reduces attack rate in MS or isolated syndromes at high risk of developing MS

Probable

Intravenous immunoglobulin

Reduces attack rate in relapsing-remitting MS

Possible

Glatiramer acetate

Reduces attack rate in relapsing-remitting MS

Possible

Methotrexate

Alters disease in progressive MS

Possible

Azathioprine

Reduces relapse rate

Possible

Cyclosporine

Some benefit in progressive MS

Possible

Plasma exchange

Severe acute episodes in previously nondisabled patients

Possible

Data from Goodin et al.42

Acute Transverse Myelitis

Acute Transverse Myelitis Th an uncommon, potentially devastating disorder associated with many illnesses (Table 18.3). Diagnostic criteria for idiopathic transverse myelitis have been published.43 It is not a likely consideration if there had been prior radiation to the spine within the last 10 years, evidence of connective tissue disease, or a variety of infectious agents.43 A vigorously mounted immune response is attributed to its pathogenesis. Demyelination and inflammation involve the spinal cord at any level, but often the effects are limited to a few segments. However, patients presenting with acute paraparesis and a distinct sensory level more commonly have extramedullary cord compression or another cause of myelitis. Chapter 12 presents the overall evaluation of acute spinal cord compression.

Clinical Presentation

Rapid ascending sensory deficit and difficulty walking within days are hallmarks of the disorder.44 Fever and nuchal rigidity may occur in 27% and 13% of patients, respectively.45 Paresthesias may be widespread, but usually a sensory level below which sensation is abnormal is pointed out by the patient.

Table 18.3. Causes of Acute Transverse Myelitis

Echovirus
Varicella
Herpes zoster
Herpes simplex (HSV1, HSV2)
Influenza
Epstein-Barr virus
Cytomegalovirus
Mycoplasma
Parasite infection (e.g., schistosomiasis)
Vaccination
Multiple sclerosis
Lupus erythematosus
Sjögren's syndrome
Syphilis
Lyme disease

Motor weakness may vary substantially, with a maximum deficit usually within 1–2 days, although subacute progression up to 2 months is known. However, maximal motor deficit may be reached within several hours.

The neurologic findings are typical of a functional cord transection at one segment, with loss of motor and sensory function and areflexia. All spinal cord levels can become involved. Partial variants have been described, with incomplete involvement, patchy and dissociated sensory symptoms, and sparing of the bladder.

Interpretation of Diagnostic Tests

Magnetic Resonance Imaging

MRI is preferred, to exclude causes that are potentially reversible. The rarity of the disorder implies that other causes of paraplegia are more frequent in clinical practice. MRI should be performed at once and, if necessary, patients should be referred to a tertiary center.

MRI findings are swelling of the cord, increased T2-weighted signal, and often abnormal enhancement throughout the cord.46,47,48,49,50

More extensive involvement may be found on MRI than is clinically evident and vice versa (Fig. 18.4). A swollen cord is difficult to differentiate from an intramedullary neoplasm or dural arterio-venous malformation causing venous hypertension (see Chapter 12), but follow-up MRI, usually within weeks, should demonstrate complete resolution or substantial improvement. MRI of the brain and visual evoked potentials are useful to demonstrate other demyelinating lesions that increase the probability of MS or Devic's disease, with acute transverse myelitis as the first defining lesion.

Cerebrospinal Fluid

CSF examination may show pleocytosis of up to 10,000 cells (both lymphocytes and polymorphonuclear leukocytes), but CSF cell count can be almost normal. CSF protein is commonly increased (in more than three-fourths of patients) and may reach values as high as 500 mg/dL.

Miscellaneous

Vasculitis (e.g., systemic lupus erythematosus) and a vascular malformation are important considerations, and spinal angiography should be performed if involvement is at a high or middle thoracic level. This localization in a spinal watershed zone may suggest a vascular rather than an autoimmune mechanism.

Figure 18.4 Acute transverse myelitis (magnetic resonance images, sagittal view). A: Long segment of T2 signal in cervical cord. B: Subtle enhancing thoracic cord abnormality. Both patients had complete cord lesions on examination.

Viral serology may be useful because well-known viruses may cause acute transverse myelitis.51

First Priority in Management

Treatment with corticosteroids is controversial. No measurable effect has been reported, and with marked variability in recovery time, improvement cannot be attributed to this treatment without a formal clinical trial. Most physicians, however, prefer a brief course with methylprednisolone (1000 mg/day).

It is unknown whether specific antibiotic or antiviral therapy improves outcome. Experience with plasmapheresis and intravenous immunoglobulin is lacking. It is important to place an indwelling catheter in patients with minimal bladder reflex activity. Dysautonomia may occur alone from a distended bladder when the lesion is above the sympathetic outflow (T6), and any stimulus may produce severe hypertension. Prophylaxis for deep venous thrombosis (heparin subcutaneously or intermittent compression devices) should begin early.

Predictors of Outcome

One-third of patients with acute transverse myelitis do not recover ambulation or bladder or bowel control. Partial recovery with a considerable handicap and good recovery each account for one-third of patients.52 Transverse myelitis has a much better prognosis if there is no progression to a complete cord syndrome and sensation remains preserved. MRI findings are not predictive of outcome. No correlation has been found with extent of the initial deficit, neurologic deficit and prognosis, and MRI findings53 (Fig. 18.4).

Triage

·     MRI of the spine on an urgent basis.

·     Neurology ward or rehabilitation unit.

Acute Leukoencephalopathy

Selective white matter damage has become more apparent with the introduction of immunosuppressive agents and chemotherapeutic agents. These lipophilic substances preferentially target myelin because of its high lipid content. MRI predominance in the bilateral parieto-occipital hemispheric regions justifies the term posterior leukoencephalopathy.54,55,56,57,58 The term posterior reversible encephalopathy syndrome (PRES) has been suggested, connotating a relationship with hypertension. This section describes acute leukoencephalopathy in adults. Causes are presented in Table 18.4. Chronic, protracted leukoencephalopathies consist of a very wide array of disorders, including aminoacidopathy, organic acid disorders, and lysosomal storage disease.

Clinical Presentation

Decrease in level of consciousness and marked cognitive decline, but also behavioral changes alone, may be presenting symptoms. Headache is prominent. Seizures are prevalent, mostly generalized tonic-clonic but focal onset has been noted. The disorder may progress rapidly to cortical blindness, marked ataxia, and speech or language abnormalities. Akinetic mutism may occur if the disorder is not recognized in the earlier stages of presentation. Akinetic mutism (summarized by Cairns et al.59 as “motionless, mindless wakefulness”) can be explained by extensive involvement of the thalamofrontal fibers and isolation of the anterior cingulate cortex.

Immunosuppressive agents (cyclosporine and tacrolimus) in transplantation recipients have been used in many well-documented cases of acute leukoencephalopathy. Breakdown of the blood-brain barrier or facilitated transport is required for these immunosuppressive drugs to enter the brain. Cyclosporine or tacrolimus may have a direct damaging effect on the vasculature, leading to microvascular damage and access to the brain.

Table 18.4. Acute Leukoencephalopathy in Adults

Immunosuppressive agents (cyclosporine, tacrolimus)
Hypertensive crises
Eclampsia, HELLP syndrome
Chemotherapeutic agents (methotrexate, 5-fluorouracil, levamisole, intra-arterial nimustine [ACNU])
Fulminant multiple sclerosis
Postradiation period
Human immunodeficiency virus encephalopathy
Erythropoietin
Interferon-
α
Heroin inhalation
Progressive multifocal leukoencephalopathy

ACNU, 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-(2-ehloroethyl)-3-nitrosourea); HELLP, hemolysis, elevated liver enzymes, and low platelet count.

Tremors, vivid visual hallucinations, and behavioral changes with paranoid behavior and wide mood swings are common and associated with rambling, nonsensible speech.60 Commonly, the speech disorder is characterized by stuttering when words are spoken rapidly or even at a normal pace but normal output when the patient is instructed to speak slowly. Speech may be distorted, with similarity to a foreign accent, and a single, generalized tonic-clonic seizure may be the only clue to toxicity. Less common presentations are blindness, cerebellar syndrome, orofacial dyskmesias, and mutism.60 Presentation is similar in tacrolimus and cyclosporine neurotoxicity: less severe signs and symptoms regress rapidly after discontinuation but may recur after a different immunosuppressive agent is substituted. With the oral microemulsion of cyclosporine (Neoral), neurotoxicity is less severe, mostly tremor and headache only.61 There are no reports of neurotoxicity with sirolimus (the term suggests a pharmacologic similarity with tacrolimus, but although receptor linkage is similar, the two agents differ in structure).

Another well-identified leukoencephalopathy has been associated with chemotherapeutic agents, predominantly 5-fluorouracil and levamisole. The estimated incidence of this toxic leukoencephalopathy is 2%.62

The lesions are more confluent and multifocal when tissue is examined. Perivascular lymphocytic inflammation is found next to demyelination. A more delayed manifestation, often with seizures, has been reported with chemotherapeutic agents. In these patients, a history of insidious decline in intellectual function is obtained together with clinical evidence of a progressive disorder characterized by spasticity and bulbar palsy. Its clinical presentation can be nothing more specific than depression and withdrawal, sometimes mistaken for a psychological response to the diagnosis of cancer. Ataxia, impaired thinking, slurring of speech, and memory impairment follow, and pro-found stupor or coma may ensue. The predominant trigger of neurotoxicity is 5-fluorouracil,62,63,64 but toxicity with levamisole alone has been reported.65

Methotrexate is used intravenously, intrathecally, and orally.66 All of these modes of administration may be associated with toxic damage to the white matter.67,68 Methotrexate barely crosses the blood-brain barrier because it is an ionized and lipid-insoluble compound, but prior radiation-induced damage to the integrity of the blood-brain barrier may facilitate its transport. Intra-arterially administered nimustine (ACNU) has produced leukoencephalopathy in the treatment of glioma.69 However, combined use of radiation and chemotherapy may complicate finding a precise cause-and-effect relationship. It may occur without prior radiation.70 The mechanism is unclear, but reversible cerebral vasospasm has been documented.71

In the management of leukemia, three recognized chemotherapy-associated leukoencephalopathy syndromes have been described: (1) an acute syndrome within 24 hours after intrathecal administration of methotrexate, cranial irradiation, or use of cytarabine, resulting in an acute confusional state and seizures resolving in 2–3 days; (2) subacute leukoencephalopathy 1–2 weeks after intravenous administration of methotrexate, with focal motor neurologic signs, behavioral changes, and seizures; and (3) insidious leukoencephalopathy progressing over months, with personality changes, marked intellectual decline, and spasticity.72

Leukoencephalopathy may occur after heroin abuse, particularly after inhalation of heroin vapor (“chasing the dragon”).73,74 Progression from cerebellar symptoms to extrapyramidal involvement to spasticity to akinetic mutism is due to involvement of both cerebral hemispheres, the cerebellar peduncles, and the midbrain.

Anecdotal reports of acute leukoencephalopathy with erythropoietin,75 amphotericin,76 and in-terferon57 have appeared. Hypertensive encephalopathy and eclampsia may cause headache, seizures, cortical blindness, and papilledema and may produce reversible posterior leukoencephalopathy syndrome.77,78

It remains important to exclude multifocal leukoencephalopathy associated with human immunodeficiency virus (HIV) and progressive multifocal leukoencephalopathy associated with JC virus by examination of CSF, polymerase chain reaction, or brain biopsy.79,80,81,82 In addition, we noted that posterior leukoencephalopathy can be the first manifestation of CNS vasculitis, with progression in other vascular territories when untreated.83 Finally a link with hypercalcemia has been suggested.84

Interpretation of Diagnostic Tests

Computed Tomography and Magnetic Resonance Imaging

CT scanning is not nearly as diagnostic as MRI in leukoencephalopathy, and a CT scan may be surprisingly normal. A comatose patient with any of the toxins or triggers mentioned above should therefore undergo MRI.

Routine MRI sequences, gadolinium enhancement, and, if available, diffusion-weighted imaging may further delineate the white matter lesion. Restricted diffusion on diffusion-weighted MRI may support cytotoxic edema, which indicates ischemia and is associated with reduced ADC values (see Chapter 9).85

The extensive lesions are nonspecific, but some MRI characteristics may point to a certain cause. These are sparing of the U fibers (cytomegalovirus and HIV encephalopathy); capping of die lateral ventricles, centrum semiovale, and corpus callosum (MS); additional gray matter involvement (central nervous system vasculitis, organic acidurias, postanoxic-ischemic encephalopathies, including carbon monoxide and cyanide); enhancement with gadolinium (ADEM, MS, Alexander's disease, Schilder's diffuse sclerosis); and sparing of the basal ganglia (lysosomal disorders, including sphingolipidosis). Several examples of acute leukoencephalopathies are shown in Figures 18.5,18.6,18.7. Most patients with mild forms of cyclosporine or tacrolimus neurotoxicity do not have MRI abnormalities,86,87 which are typically seen in the most severe instances,88,89,90 often in patients with seizures at presentation. Progressive multifocal leukoencephalopathy may mimic these disorders. Little or no mass effect or gadolinium enhancement is noted. The lesions are in focal areas of the gray-white junction (Fig. 18.8).

Figure 18.5 Magnetic resonance images demonstrate radiation leukoencephalopathy (radiation for glioma).

Cerebrospinal Fluid and Serum

CSF examination is useful to obtain material for detecting the JC virus, and the test has 100% specificity in immunosuppressed patients after transplantation. Oligoclonal bands and IgG index are not diagnostic and can be seen in many demyelinating disorders.

The correlation of cyclosporine and tacrolimus with blood or plasma levels is unreliable, and in some patients progression may occur despite declining blood levels. In only 30%–40% of reported cases, trough plasma levels are increased or show a significant upward trend. Plasma levels of these immunosuppressive agents are more likely to be increased when leukoencephalopathy is demonstrated on MRI, but correlation remains poor.

Figure 18.6 Methotrexate leukoencephalopathy on axial T2-weighted (A) and sagittal fluid-attenuated inversion recovery (B) magnetic resonance imaging (similar findings possible with 5-fluorouracil and levamisole).

First Priority in Management

Discontinuation of therapy with the causative drug may resolve most of the symptoms within 2 days. Cyclosporine or tacrolimus can be replaced by mycophenolate mofetil (CellCept) or sirolimus. Methylprednisolone (1 g for 3–5 days) has been administered intravenously in inflammatory leukoencephalopathies associated with chemotherapeutic agents, with a successful result but no proof of its effect.65 Suspicion of progressive multifocal leukoencephalopathy should be high in patients who have acquired immunodeficiency syndrome (AIDS) and in transplantation recipients. Treatment with cytarabine (2 mg/kg) should await biopsy determination, but it may retard progression only for several months.

Figure 18.7 Cyclosporine-associated leukoencephalopathy, with multiple areas of involvement but normal diffusion-weighted imaging, suggesting edema.

Predictors of Outcome

The prognosis for complete recovery in drug-associated leukoencephalitis is excellent, and both clinical resolution and MRI resolution are expected after cessation of the immunosuppressive and chemotherapeutic agents. Incomplete recovery has been noted, however, particularly in comatose patients.62 The median survival with progressive multifocal leukoencephalopathy in HIV infection is 10 weeks, but survival appears prolonged when leukoencephalopathy emerges in patients receiving highly active antiretroviral therapy, increasing to 46 weeks.91

Figure 18.8 Focal posterior leukoencephalopathy due to biopsy-proven progressive multifocal leukoencephalopathy.

Triage

·     Most patients can be treated with supportive care on the ward.

·     Status epilepticus or focal partial status epilepticus is very uncommon, but a prolonged series of seizures may justify 24-hour observation with video and electroencephalographic monitoring in an intensive care unit.

References

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2. Mills RW, Schoolfield L: Acute transverse myelitis associated with Mycoplasma pneumoniae infection: a case report and review of the literature. Pediatr Infect Dis J 11: 228, 1992.

3. Sacconi S, Salviati L, Merelli E: Acute disseminated encephalomyelitis associated with hepatitis C virus infection. Arch Neurol 58:1679, 2001.

4. Carrigan DR, Harrington D, Knox KK: Subacute leukoencephalitis caused by CNS infection with human herpes-virus-6 manifesting as acute multiple sclerosis. Neurology 47:145, 1996.

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