Chapter 9: Inflammatory and Demyelinating Central Nervous System Diseases

The constellation of fever, generalized weakness, and bulbar dysfunction can be from a multitude of diseases. Grouping them according to location of disease is useful in guiding diagnostic tests that are needed. Infectious etiologies for central nervous system (CNS) dysfunction (ie, meningitis, encephalitis, cerebral abscess) are important to diagnose and treat quickly. Given the emergent necessity of treating infectious etiologies of meningitis and/or encephalitis, it is prudent to begin treatment with antiviral and antibacterial agents while diagnostic testing proceeds. Intravenous acyclovir should be strongly considered as well as intravenous medication to treat bacterial meningitis, tuberculosis, and fungal infections, depending on clinical suspicion. Diagnosis and treatment of infectious diseases will be discussed in Chapter 7. To diagnose CNS infection, a lumbar puncture should not be delayed.

Although unlikely in this case, perhaps the most time-sensitive diagnosis would be a vascular etiology. In a patient with vascular risk factors and cranial nerve signs/symptoms, a posterior circulation ischemic event is most important to diagnose quickly. Although a noncontrast head CT is effective in diagnosing intracerebral hemorrhages, in this setting it is probably not very helpful. Magnetic resonance imaging (MRI) of the brain is the most effective tool for diagnosing ischemic strokes and also will help in diagnosing other diseases.

Once infectious and vascular etiologies are addressed, one must consider inflammatory diseases. The history of symptoms occurring after a viral prodrome, malaise, and low-grade fever is suggestive of a postinfectious inflammatory process. Acute disseminated encephalomyelitis (ADEM) is a disease that can cause rapid mental status changes and multifocal neurologic deficits. An MRI with and without gadolinium is necessary to diagnose ADEM.

Other possible parenchymal diseases include metastatic disease, other autoimmune inflammatory diseases such as tumefactive multiple sclerosis (MS), and CNS manifestations of systemic autoimmune diseases: lupus, Behçet syndrome, vasculitis, and paraneoplastic diseases.

Leptomeningeal processes can cause encephalopathy and multifocal neurologic symptoms. Again, infectious processes are the most urgent to diagnose. Other possibilities are inflammatory diseases such as sarcoid, neoplastisms, and carcinomatous meningitis.

Although the patient's encephalopathy suggests otherwise, another important location of disease can be in the peripheral nervous system. Demyelinating diseases such as Guillain-Barré syndrome (GBS) can progress over days and impair bulbar function. In fact, some diseases can affect both the central and peripheral nervous systems to produce this clinical syndrome. Bickerstaff encephalitis, a variant of GBS, involves ophthalmoplegia, ataxia, and encephalopathy. It is associated with peripheral motor axonal demyelination with brainstem encephalitis. The detection of the antiganglioside immunoglobulin G (IgG) GQ1b antibody is helpful in the diagnosis of this disease.¹ In a recent case series of patients with ADEM, 43% had polyradiculoneuropathy; mostly demyelinating.² If there is clinical suspicion for peripheral involvement, electromyography and nerve conduction studies (EMG/NCSs) are warranted. Patterns seen on EMG/NCS are discussed in Chapter 6.

The patient underwent a lumbar puncture that showed: 10 white blood cells (WBCs); 67% lymphocytes; 33% monophils; 0 red blood cells (RBCs); glucose 65; protein 80; albumin index 11.4 (elevated); herpes simplex virus polymerase chain reaction (HSV PCR) negative; no detected oligoclonal bands; bacterial cultures negative; encephalitis panel negative; paraneoplastic panel negative.

The MRI showed multiple bilateral lesions in the white matter of both hemispheres and large lesions affecting the basal ganglia and thalamus with minimal mass effect (Figure 9-1). This suggested a multifocal disease process affecting mostly white matter and deep gray matter.

ADEM is a disease of multifocal white matter demyelination. The typical clinical description of ADEM includes a rapid onset of progressive encephalopathy associated with multifocal neurologic deficits. The clinical syndrome is usually preceded by an antecedent infection or vaccination. A prodromal phase with fever, headache, and malaise may precede the full clinical syndrome.³ Although more commonly seen in the pediatric population, it is also encountered in adults. The most commonly used definition has been published by the International Pediatric MS Study Group. ADEM: “A first clinical event with a polysymptomatic encephalopathy, with acute or subacute onset, showing focal or multifocal hyperintense lesions predominantly affecting the CNS white matter; no evidence of previous destructive white matter changes should be present; and no history of a previous clinical episode with features of a demyelinating event… .”³

MRI findings of ADEM have been extensively characterized. Lesions are typically large, multiple, asymmetric, and involve subcortical and central white matter, located at the gray-white junction in the hemispheres, cerebellum, and brainstem. Gadolinium enhancement is variable. Patterns can be complete ring enhancing, nodular, gyral, or spotty. As opposed to multiple sclerosis, the deep gray matter can be involved, especially the caudate head, globus pallidus, putamen, and thalamus. Four types of lesions have been described: (1) small lesions (less than 5 mm), (2) large, confluent, or tumefactive lesions, with edema and mass effect, (3) additional symmetric bithalamic involvements, and (4) acute hemorrhagic encephalomyelitis.^3-6

In our patient, cerebrospinal fluid (CSF) analysis showed no evidence for an infectious process. A mild pleocytosis and an elevated protein with no oligoclonal bands are characteristic of ADEM.^3,6,7

Another possibility is progressive multifocal leukoencephalopathy (PML). PML is a disease that is multifocal and involves mostly the white matter. As our patient is human immunodeficiency virus (HIV)-negative and has no history of immune suppression, PML would be exceedingly unusual. CSF testing for the presence of the JC virus is helpful with the diagnosis.⁸

No randomized clinical trials exist to guide our management for patients with ADEM. Most treatment options are extensions from experience with other demyelinating, autoimmune diseases. Intravenous, methylprednisolone 1 g per day for 3 to 5 days is the typical treatment of choice. The response to steroids can be dramatic, but up to one-third of patients may not respond. Patients with aggressive forms of ADEM may be less likely to respond to steroid treatment.^9,10

Aggressive ADEM with disease progression to the point of respiratory failure and admission to the NICU is infrequent occurring in less than 20% of ADEM cases.^6,11 As the complications of mechanical ventilation and immobility compound with time, the speed of recovery needs to be emphasized. This argues for an aggressive treatment strategy.

Immune-modulating treatments, intravenous immune globulin (IVIG), and plasmapheresis (PE) are the next steps in management. IVIG has been used more widely. The usual dose of 0.4 g/kg per day for 5 days has been shown to be efficacious in case series. Improvement usually begins within a week and progresses until 2 months.^9,10,12,13 Although the mechanism for the efficacy for IVIG is not fully understood, it is thought to work by blocking the Fc-receptor on macrophages and effectively decreasing the cell-mediated immune response.^14-16 In addition to direct immune effects, it may work by helping to normalize the blood-brain barrier.¹⁷ Some have debated that in cases of severe disease with peripheral nerve involvement, IVIG along with IV steroids should be first-line therapy.¹³

PE has also been used in ADEM, and a number of case reports support its use. PE is thought to work by removing humoral factors and affecting the balance of B cells and T helper type 1 and type 2 cells.^15,18 In a randomized study of PE in patients with acute CNS inflammatory demyelinating disease, PE was associated with improved neurologic recovery.¹⁹ Other case studies also support the use of PE in CNS demyelinating disease and specifically in ADEM patients. In general, about half of patients will respond. Factors associated with improvement are early treatment and male gender.^20,21

If a patient does not improve after the first intervention regardless of whether IVIG or PE was performed, the other intervention in addition should be considered. Although no substantial evidence supports treatment with both PE and IVIG, some have suggested that it is more effective.^10,15

In fact, for patients who are severely affected in the NICU, IV steroids should be started immediately. If little or no clinical response is observed in the first several days, PE should be started for a total of five to seven sessions. If the patient is still critically ill, IVIG should be instituted. PE should be attempted first because of the evidence of efficacy in CNS demyelinating disorders as opposed to the limited evidence behind IVIG. A secondary advantage of treating with PE first is the theoretical advantage of first removing humeral factors through PE and subsequently adding IVIG. Although IVIG is technically easier, if PE is added as a second agent, PE will wash out the previously administered IVIG. If no response to steroids is seen in the first several days of treatment, escalation to immune-modulating therapy should occur quickly as PE and IVIG are more effective the sooner they are started in the time course of the disease.

Other immune-modifying treatments including cyclophosphamide, interferon beta, glatiramer acetate, and rituximab have been suggested, but to date no large series of ADEM patients undergoing these treatments have been described. Owing to the rarity and refractory nature of ADEM in these patients, efficacy may be difficult to assess. Although treated with intravenous Solu-Medrol for 5 days, PE, and IVIG, this patient did not clinically improve. The MRI with diffusion tensor imaging showed atrophy of white matter tract across time (Figure 9-2).

Biopsy of the ADEM lesions is warranted when the disease does not respond to conventional treatments (ie, IV steroids, IVIG, or PE) and the presentation is atypical in that other infectious etiologies or neoplastic processes have not been ruled out. The hallmark of ADEM on biopsy is perivenous demyelination as opposed to confluent demyelination, which is seen in acute multiple sclerosis.²²

Although diagnostic studies are important, just as important in this case is treatment of seizures. Treatment of status epilepticus is discussed in Chapter 3.

In a patient who presents with altered mental status, fever, and seizure, infectious encephalitis is the most important disease to diagnose and treat. HSV encephalitis caused by herpesvirus should be presumptively treated with IV acyclovir. An extensive workup for other infectious encephalitides should be performed. Other noninfectious causes of encephalitis are inflammatory and paraneoplastic.

Paraneoplastic syndromes and autoimmune-mediated encephalitis are a group of disorders that can be challenging to diagnose and treat. The first step in managing a patient with a possible paraneoplastic syndrome is to identify the neoplasm and the associated autoantibody. CT of the chest, abdomen, and pelvis looking for masses; peripheral blood studies to diagnose hematologic neoplasms, and nuclear radiologic studies (positron emission tomography [PET], single-photon emission computed tomography [SPECT], and metaiodobenzylguanidine [mIBG] scans) can be preformed. A list of paraneoplastic neurologic diseases causing encephalitis is provided in Table 9-1.

A CT of the abdomen and pelvis looking for masses showed an ovarian mass suggestive of a teratoma. A transvaginal ultrasound confirms the findings.

Anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis is a disease that has been recently characterized. Usually affecting women under 40 years of age, patients develop prominent psychiatric symptoms and behavior changes that progress to orofacial dyskinesias, seizures, encephalopathy, autonomic instability, respiratory failure, and a catatonia-like state. When first described, almost all patients had an associated ovarian teratoma. Now it is recognized that up to 60% of patients may not have a detectable tumor.^28,34 Although the prevalence is unclear, some suggest that NMDAR encephalitis may account for a significant number of unexplained new-onset epilepsy in women before the age of 40.^35,36

NMDAR encephalitis is associated with antibodies against the NR1-NR2 heteromers of the NMDAR. The detection of these antibodies in the serum or CSF is diagnostic.^28,37 The disease is characterized by prominent microgliosis and deposits of IgG in the hippocampus, forebrain, basal ganglia, and spinal cord. NMDAR-expressing neurons with inflammatory infiltrates can be found in the teratomas. In addition, cytotoxic markers are extremely uncommon, suggesting that the antibody immune response is the primary mechanism of damage and cell death. Severity of disease is related to levels of antibody titers.^37,38

Although intrathecal production of antibodies has been described, the antibodies to the NMDAR presumably start in the serum. How the antibodies cross the blood-brain barrier is unclear. The amygdala and hippocampus have the highest levels of NMDAR and are also the brain regions where the blood-brain barrier is the most vulnerable. It has been proposed that the dysautonomia with episodes of sympathetic overactivity and hypertension may weaken an already damaged blood-brain barrier and make these regions even more susceptible.³⁷

MRI is nonspecific but approximately 55% of patients have increased fluid-attenuated inversion recovery (FLAIR) or T2 signal in brain parenchyma (Figure 9-3).²⁸ N-acetylaspartate (NAA) levels in the basal ganglia and thalamus have been shown to be reduced during involuntary movements. Diffusely the brain has a decreased NAA/Cr ratio, suggesting diffuse brain dysfunction. MR perfusion shows hyperperfusion diffusely.³⁹

Similar to other paraneoplastic diseases, tumor resection and immune suppression are the mainstays of treatment. Identification and removal of the teratoma is probably the most effective treatment.^34,40 In addition to tumor removal, immune suppression is commonly performed. Most patients receive IV corticosteroids and IVIG or PE depending on disease severity. For patients in the NICU we recommend early and aggressive treatment. Early detection and removal of the teratoma is paramount. For immune suppression, methylprednisolone 1 g IV for 5 days should be given. After tumor removal and steroids, if no clinical change is seen in the first few days, PE for five to seven sessions should be strongly considered. If no clinical change occurs after PE, serum and CSF should be reanalyzed for the presence and titers of anti-NMDAR antibodies. In addition, IVIG should be given at this time.^34,41, If titers are still elevated and no clinical improvement is observed, rituximab or cyclophosphamide should be used.³⁴ Standard chemotherapeutic agents bleomycin, etoposide, and cisplatin have also been used successfully.^42,43 In patients without a detected teratoma, immune modulation/suppression is needed with the same algorithm. In addition, routine monitoring for tumor occurrence with MRI of the pelvis is recommended.⁴⁴ In patients with refractory encephalitis not responsive to aggressive treatment, prophylactic bilateral ovariectomy without evidence of teratomas has been performed as a lifesaving intervention. The efficacy of this treatment has not been established.

Much attention has been given to the bizarre movements seen in this disorder as it can be very striking and difficult to control. Because many times the treatment of the movement disorder can be difficult and the side effects of medications substantial, treatment of movements should be treated with caution and only if medically necessary. Symptomatic treatment with benzodiazepines, usually long-acting agents such as clonazepam, typical neuroleptics including haloperidol, and atypical neuroleptics such as quetiapine have been used. In several patients, only induction doses of propofol and benzodiazepines effectively controlled the movements. In addition, because of the intense jaw clenching that occurs, botulinum toxin injections to the jaw have been performed.

As opposed to many of the other paraneoplastic diseases, the importance of identifying this disease is that the prognosis is generally good. Although tumor removal has been shown to be effective in treating NMDAR encephalitis, even without tumor removal full recovery after years of follow-up has been described.⁴⁴ In the most comprehensive case series of 100 patients, 75 patients recovered to normal or had only mild deficits.²⁸ However, cases severe enough to be admitted to the NICU most likely have a worse prognosis. Because of the evidence that early treatment improves outcomes and the high number of medical complications that occur in these patients, early and aggressive treatment is recommended.

In patients with refractory encephalitis, a devastating neurologic disease with significant brain atrophy and semi-vegetative state has been seen.