10: Autoimmune dementias

Andrew McKeon and Sean J. Pittock

Mayo Clinic, Rochester, MN, USA

Introduction

In the evaluation of a patient with cognitive decline, clinicians should consider the possibility of an autoimmune etiology on their list of differential diagnoses. The importance of not overlooking this possibility rests in the experience that these patients have a potentially immunotherapy-responsive, reversible disorder [1].

Traditionally, neurologists have usually considered autoimmune dementias within the framework of subacute-onset delirium and limbic encephalitis only. The development and widespread availability of neural antibody marker testing has changed this perspective so that other presenting symptoms such as personality change, executive dysfunction, and psychiatric symptoms are increasingly recognized in an autoimmune context. Clues that are helpful in identifying patients with an autoimmune dementia can be summarized within a triad of (i) suspicious clinical features (a subacute onset of symptoms, a rapidly progressive course, and fluctuating symptoms) and radiological findings, (ii) the detection of CSF or serological biomarkers of autoimmunity, and (iii) a response to immunotherapy (see Table 10.1 for Key Points). This rapidly evolving field is still in its infancy, and much of the clinical data, including that related to treatment and outcomes, is documented in single cases or small retrospective cases series only.

Table 10.1 Key points for autoimmune dementias.

Clinical manifestations are diverse and often multifocal

Personal history or family history of autoimmunity or cancer might provide important diagnostic clues

Antibodies targeting nonneural antigens (e.g., thyroid, antinuclear) serve as clues for neurological autoimmunity, but do not provide a definitive diagnosis

Neural-specific autoantibodies serve as markers of neurologic autoimmunity and cancer

A trial of immunotherapy (steroids, IVIG, and/or plasma exchange) serves as a diagnostic test. Trials of multiple treatment types may be required

Autoimmune dementias are frequently relapsing and immunotherapy over years may be required

Nomenclature

Diagnostic terms often used to describe such patients include “autoimmune encephalopathy” (which implies delirium is present) and autoimmune dementias (where there is no delirium) and immunotherapy-responsive encephalopathy (as these patients typically have improvements after treatment with corticosteroids). For brevity’s sake, we will refer to autoimmune cognitive impairment with or without encephalopathy as autoimmune dementia throughout this chapter. The nomenclature pertaining to autoimmune dementias can seem confusing. Disorders have been classified with respect to clinical phenotype (e.g., progressive encephalomyelitis with rigidity and myoclonus [aka PERM]) [2], eponym (Morvan’s syndrome) [3], pathology (e.g., nonvasculitic autoimmune meningoencephalitis (NAIM)) [4], or associated antibody (e.g., the N-methyl-D-aspartate receptor (NMDAR) antibody-associated encephalitis) [5]. In some instances, there is more than one name in the literature for a particular disorder; both Hashimoto encephalopathy [6] and steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) [7] refer to the same entity: a triad of cognitive problems, thyroid antibodies detected serologically, and established clinical improvement with immunotherapy. While each description contributes something to our understanding of these disorders, from the standpoint of the practicing neurologist, immunotherapy responsiveness unites these and other autoimmune dementias.

Epidemiology

The incidence and prevalence of autoimmune dementias are unknown. They are thought to be rare but are likely underrecognized. An autoimmune or inflammatory cause of cognitive decline accounts for 20% of dementia in patients under 45 years of age [8].

Case 1

A 58-year-old man with a remote history of thyroid carcinoma, in remission, presented with acute onset of word-finding difficulty and memory problems when giving a presentation to colleagues at work. His evaluation included an MRI of head which demonstrated a left temporal T2 signal abnormality (Figure 10.1a) and an EEG which demonstrated left temporal epileptiform discharges. Neuropsychometric evaluation was remarkable for poor performance on mainly verbal memory scores. Serological evaluation revealed voltage-gated potassium channel (VGKC) complex antibodies, with value of 1.00 nmol/L (normal, ≥ 0.02 nmol/L). PET–CT imaging of body did not demonstrate any new carcinoma. He received intravenous methylprednisolone infusions (1000 mg) daily for 5 days, followed by weekly for 6 weeks. He improved considerably and was “90% better.” At that stage, the methylprednisolone dosing interval was widened to one dose every other week. Within 2 weeks, he and his wife noted that he was regressing considerably with respect to memory. He also became emotionally labile and depressed. Repeat MRI imaging demonstrated atrophy of the left hippocampus and new T2 signal abnormality in the right hippocampus (Figure 10.1b). He was treated with seven exchanges of plasmapheresis over 14 days and noted marked improvements. These improvements continued over the next 3 months on prednisone 60 mg by mouth daily. In addition, azathioprine was initiated at 2.5 mg/kg/day as a remission-maintaining drug (mycophenolate mofetil, methotrexate, and hydroxychloroquine are alternatives in this situation; there is no evidence to support the use of one drug over the other). Surveillance neuropsychological evaluation revealed improvements in memory scores almost to within the normal range, although his MRI had not changed. He remained in remission as prednisone alone was tapered slowly over the following 6 months.

Figure 10.1 Case 1: FLAIR axial MRIs (radiological orientation). (a) At initial symptom onset, T2 signal abnormality is seen in the left hippocampus. (b) After relapse, T2 signal is less prominent in the left hippocampus. New, subtle T2 signal abnormality is now seen in the right hippocampus (arrow). Bilateral temporal lobe atrophy is seen. See text.

Case 2

A 47-year-old woman presented with subacute onset of psychosis and severe headaches in 2001. Investigation revealed a lymphocytic pleocytosis on CSF (other CSF data was not available) and a normal MRI brain scan. After 3 months of persistent symptoms despite standard psychiatric treatments, she was treated with steroids empirically and improved significantly but had residual cognitive problems (impairments of verbal intellect, problem solving, visuospatial appreciation, memory and cognitive speed) preventing her return to work. She remained stable with moderate cognitive impairment from early 2002 until November 2009 when she had acute onset of confusion, worsening amnesia, agitation, crying, visual and auditory hallucinations, and behavioral disturbance. She also had one generalized seizure. Again, her CSF demonstrated a lymphocytic pleocytosis with 100 white cells, and oligoclonal bands were present. MRI imaging was unremarkable. CSF paraneoplastic evaluation sent to the Mayo Clinic Neuroimmunology Laboratory identified NMDAR antibodies (Figure 10.2). Evaluations for teratoma including clinical examination, pelvic ultrasound, PET imaging, and finally pathology (after bilateral salpingo-oophorectomy and hysterectomy) were all negative for cancer. She subsequently received intravenous methylprednisolone for 3 days and then five treatments of plasma exchange over 10 days and had marked improvements. The behavioral outbursts, crying, confusion, and agitation ceased. Her cognition improved back to her premorbid 2009 baseline of moderate generalized dysfunction. Maintenance therapy included a slow taper of oral prednisone over 9 months and ongoing maintenance of azathioprine (2.5 mg/kg/day).

Figure 10.2 NMDAR antibody (relevant to Case 2). Indirect immunofluorescence staining pattern of patient’s serum on a composite of mouse neural tissue, provided courtesy of Dr. Vanda A. Lennon, Neuroimmunology Laboratory, Mayo Clinic, Rochester, MN. Hippocampus (Hi) stains brighter than cerebral cortex (Co), basal ganglia (BG), and thalamus (Th). Granular layer (GL) of cerebellum also stains brightly, typical for NMDAR antibody; molecular layer (ML) is negative.

Clinical features

Symptoms

Autoimmune dementias typically have a subacute onset with progression more rapid than would be expected for most neurodegenerative disorders, with the exception of Creutzfeldt–Jakob disease (CJD). While limbic encephalitis (a fluctuating confusional state accompanied by one or more of seizures, agitation, memory loss, and hallucinations) is the best recognized clinical presentation [9], other symptoms of dementia including apraxia, aphasia, behavioral change, and disturbances in orientation and reasoning have been reported [10–12]. Delirium (impaired attention and consciousness) is a common, but not universal, presentation. Marked fluctuations in the clinical course and spontaneous remission suggest an autoimmune cause but can also be seen in patients with toxic and metabolic causes of dementia, in patients with psychogenic disorders, and in patients with depression.

A sleep history may also be informative. Patients with Ma2 antibody encephalitis might complain of hypersomnia [13]. Conversely, patients with voltage-gated potassium channel-complex autoimmunity often complain of insomnia [14]. Patients with sleep apnea syndrome (either central or obstructive) typically have fluctuating cognitive complaints related to a lack of restorative sleep rather than an autoimmune dementia [15]. A fluctuating mental state accompanied by a sleep disorder and parkinsonism can be seen in diffuse Lewy body disease [16] (see Chapter 6).

In some disorders, characteristic noncognitive features are important also. For example, in a patient with a history of visual loss and hearing loss, in addition to cognitive symptoms, Susac’s syndrome (an immunotherapy-responsive endotheliopathy) should be considered [17]. Other symptoms and signs common in Susac’s syndrome include memory loss, psychiatric symptoms, and headache. Patients with mitochondrial disorders can also present with fluctuating encephalopathies and visual and hearing impairments.

Past and family history

This information is crucial. A history of cancer may be relevant, since an autoimmune, paraneoplastic dementia may be the herald of a recurrence of cancer. Patients with autoimmune dementia frequently have one or more coexisting autoimmune disorders, such as hypothyroidism, SLE, and rheumatoid arthritis. Likewise, a smoking history, review of systemic symptoms, and a family history of autoimmunity and cancer might be informative.

Examination findings

Impairments in one or more categories of attention, memory, reasoning, calculation, and praxis can be documented using brief bedside evaluations such as the MMSE [18], the Montreal Cognitive Assessment (MoCA; www.mocatest.org), or the Kokmen Short Test of Mental Status [19]. More extensive neuropsychological testing, however, is often required to fully characterize the degree of cognitive impairment. This serves both to document the abnormalities present and as a pretreatment baseline. Since autoimmune neurological disorders are often multifocal [20, 21], other neurologic symptoms and signs may accompany the cognitive impairment. These may include seizures, ataxia, brainstem signs, parkinsonism, myoclonus, tremor, myelopathy, or a peripheral nervous system disorder.

Differential diagnoses

Both potentially reversible etiologies (Table 10.2) and neurodegenerative causes for cognitive symptoms need to be considered. Unlike autoimmune dementias, neurodegenerative disorders, with the exception of prion diseases, are usually characterized by indolent onset and slow progression over years. Neurodegenerative disorders include Alzheimer disease, frontotemporal dementia, diffuse Lewy body disease, Parkinson’s disease with dementia, progressive supranuclear palsy, and corticobasal degeneration (see Chapters 3, 5–7, and 9). Mitochondrial diseases can also lead to dementia but often have other distinguishing features, such as retinopathy, hearing loss, short stature, and/or neuropathy (www.genetest.org). Among the treatable causes to consider (Table 10.2) are some other idiopathic inflammatory disorders that are also immunotherapy responsive. Each has well-characterized clinical, radiologic, and pathologic diagnostic features and recommended treatments. Examples include multiple sclerosis, CNS vasculitis (also known as primary angiitis of the CNS), sarcoidosis, and neuro-Behçet’s disease.

Table 10.2 Potentially reversible causes of cognitive impairment.

Potentially reversible causes of cognitive impairment	Examples
Cancer (neoplasia)	Primary CNS lymphoma (including intravascular and meningeal presentations)
Autoimmune encephalopathies and dementias	Immunotherapy-responsive disorders of presumed autoimmune etiology
Psychiatric illness	Anxiety, depression, psychosis
Toxic	Alcohol, opiates, cocaine, amphetamines, organic solvents
Inflammatory CNS disorders (other than autoimmune)	Multiple sclerosis, acute disseminated encephalomyelitis, neurosarcoidosis, neuro-Behçet’s disease
Vasculopathies	CNS vasculitis, posterior reversible leukoencephalopathy (PRES), subdural hematoma, venous thrombosis
Endocrine	Disturbances in pituitary, thyroid, parathyroid, endocrine pancreatic, or adrenal function
Metabolic	Respiratory, renal or liver failure. Obstructive sleep apnea syndrome. Mitochondrial disorders^* (e.g., MELAS)
Infection of the central nervous system	HSV, HHV-6, HIV, fungal (e.g., cryptococcus), mycobacterial, Whipple’s disease, neurosyphilis
Nutritional deficiency	Vitamin B12, vitamin E, thiamine, folic acid,
Drugs	Benzodiazepines, antidepressants, antipsychotics, antiepileptics, analgesics
Seizure disorders	Nonconvulsive status epilepticus

The anagram CAPTIVE MINDS may aid memory.

^* Mitochondrial diseases can remit, although they are not currently treatable or reversible.

During an MS relapse, a patient may develop subacute cognitive symptoms with delirium and impaired attention, and subsequent improvements may occur during remission [22].

Headache and rapidly progressive dementia are two characteristic presentations of CNS vasculitis [23]. The diagnosis is aided by cerebral angiography and definitively proven by demonstrating multifocal inflammation and necrosis of small arteries, primarily in the leptomeninges; some have a coexisting amyloid angiopathy. This type of biopsy might be necessary to rule out intravascular lymphoma, which can have similar angiographic findings to CNS vasculitis [24].

Although noncognitive deficits (such as cranial neuropathies) are most common in CNS sarcoidosis, some patients may present with cognitive deficits [25]. The diagnosis often proves elusive in patients without systemic disease, and brain biopsy may be required to establish the pathological hallmark of an inflammatory infiltrate with noncaseating granulomas.

Behçet’s disease is characterized by uveitis, oral aphthae, and genital ulcerations. Presentations of neuro-Behçet’s disease may include a rapidly progressive subcortical dementia characterized by amnesia and a frontal dysexecutive syndrome [26]. In addition, patients can present with pyramidal tract, spinal cord, and sphincter dysfunction. Brain MRI often reveals focal or diffuse T2-weighted hyperintensities, particularly in the basal ganglia, thalamus, upper brainstem, and mesial temporal structures [26].

Rarer infiltrative, inflammatory disorders of the central nervous system, which may be steroid responsive, include Langerhans cell histiocytosis [27], crystal-storing histiocytosis [28], and lymphomatoid granulomatosis [29].

Neurological Testing

Defining abnormalities with objective tests: Neuropsychological testing, imaging, and EEG

There are several components to testing when evaluating a patient with autoimmune dementia. Some testing aids with documenting objective abnormalities, which serves as a baseline before a trial of treatment is undertaken. Resolution of neuropsychological, EEG, MRI (Figure 10.3), or functional imaging abnormalities after immunotherapy serves as an objective marker supporting patient-reported improvements.

Image described by caption. — **Figure 10.3** FLAIR axial MRIs in a patient with LGI1 (“VGKC”) antibody and limbic encephalitis with left greater than right medial temporal lobe hyperintensities **(a)** that had radiologic and clinical improvements **(b)** after corticosteroid therapy.

Source: McKeon et al. [1]. Reproduced with permission of Wolters Kluwer.

Neuropsychological testing, in particular, provides a detailed assessment of deficits and can be very informative in mild cases where the abnormalities are subtle. In addition, other mitigating factors leading to cognitive complaints (such as depression) can be identified by a neuropsychologist. Unfortunately, there is a dearth of literature on the precise cognitive profile of patients with autoimmune dementia. Comprehensive cognitive testing, however, is probably best, including evaluation of memory, frontal-executive function, and processing speed [12].

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