Most dementias develop slowly, allowing an unhurried outpatient evaluation. Algorithms for the assessment of these patients have been developed and refined, and most neurologists are well acquainted with these approaches. A careful history will usually detect dementia secondary to medications or depression and routine laboratory assessments help to eliminate metabolic conditions that can cause dementia including anemia, electrolyte imbalance, liver or kidney failure, thyroid disease and vitamin B12 deficiency. The majority of slowly progressive dementias are secondary to Alzheimer's disease (AD), although there is an increasing recognition of non-AD dementias, including frontotemporal dementia (FTD; see Chapter 1), subcortical ischemia vascular disease (SIVD; see Chapter 8), dementia with Lewy bodies (DLB; see Chapter 9), and other parkinsonian dementias such as cortical basal degeneration (CBD) and progressive supranuclear palsy.[3] (see Chapter 11). However, with the possible exceptions of DLB and CBD, the disorders that commonly lead to slowly progressive adult dementia, such as AD and FTD, rarely present as RPDs. [4-6] The patient with an RPD often requires consideration of a different set of disorders.

The primary aim of this chapter is to instruct clinicians in an approach to the differential diagnosis of RPD that will broaden their scope of inquiry and, particularly, to identify RPDs that are treatable and potentially reversible. We have organized this chapter around the following categories: neurodegenerative, autoimmune, toxic/metabolic, infectious, neoplastic, vascular, and we will emphasize the RPDs that are most difficult to diagnose or least likely to be recognized. As many types of conditions can cause RPD and they can progress quickly, it is important to have an organized, systematic approach to diagnosis. The mnemonic VITAMINS is often useful for summarizing some of the major categories of etiologies for RPDs (Table 13.1). Table 13.2 lists many etiologies of RPD, many of which there is unfortunately not space to discuss in this review. When considering an RPD patient, it may be helpful to use these tables to ensure a complete differential has been considered. RPDs that present with space occupying brain lesions easily identified by CT or MRI scan, are not discussed in this chapter. Figures 13.1 and 13.2 provide an outline for the diagnostic approach that we use in evaluating a patient with RPD. Figure 13.1 shows the overall approach, while 13.2 details an expanded evaluation when standard testing is inconclusive.

Parkinsonian dementias, such as DLB and FTD-spectrum disorders including PSP, CBD and FTD are discussed in Chapters 1, 2 and 11 and thus will only will be briefly mentioned here. DLB is a progressive dementia often associated with fluctuations in cognitive function, persistent well-formed visual hallucinations, and/or parkinsonism. [27] Duration of DLB is often shorter than for many other neurodegenerative dementias; one study suggests 3 year survival [28], although rapid decline with death in one year can occur. Periodic sharp waves may be seen on EEG, leading to confusion with CJD. [26, 29]. In several large cohort studies, DLB was the second most common condition mistaken for CJD.[4, 26] FTD is rarely rapidly progressive, although it typically has a faster course than AD. Patients typically present with a frontal syndrome including behavioral, personality and cognitive changes occurring over years, followed by dementia. Fifteen percent or more of FTD patients develop amyotrophic lateral sclerosis (ALS) and these patients typically die within 1.4 years from the time of diagnosis. [30-33] Corticobasal degeneration (CBD) is a clinically and pathologically heterogeneous atypical parkinsonian dementia often confused clinically with AD, PSP, or FTD. [34-38] Many features of CBD, including myoclonus, alien limb and visual, sensory and motor deficits overlap with features of CJD. The converse is also true; CJD can sometimes present as a rapid cortical basal syndrome (CBS) [39] or with a protracted course over two to three years with features indistinguishable from CBD; however, the FLAIR and DWI MRI abnormalities seen in CJD are not found in CBD.[40] As in CJD, PSP patients develop dementia, akinetic-rigid parkinsonism (symmetric bradykinesia and axial rigidity), postural instability, swallowing and speech problems, and often progress to a hypokinetic, mute state. [41-46] Abnormalities of eye movements, particularly slowed of velocity of saccades progressing to supranuclear gaze palsy, are part of the PSP syndrome. CJD mimicking PSP has been reported.[47]

Neurofilament inclusion body disease (NIBD) is a recently described pathologic condition that can clinically present as FTD or CBD. The four index cases were all more rapid than typical degenerative dementias, with duration of only two to four years. Brain MRI and pathology showed frontal, temporal and caudate atrophy. A distinguishing feature of NIBD is the presence of intracytopasmic neuronal inclusions that stain strongly with antibodies to neurofilament proteins and ubiquitin, but not tau or α-synuclein.[48] Once case of NIBD has also presented as an early onset rapidly progressive FTD with features of primary lateral sclerosis.[49]

Paraneoplastic neurologic disorders (PNDs) often present as a rapidly progressive limbic encephalopathy. PNDs that involve the CNS are often divided into two forms: those with isolated involvement of one part of the nervous system (e.g., limbic encephalitis/ encephalopathy, cerebellar syndromes, retinal degeneration) or those with more diffuse, multifocal symptoms, sometimes referred to as paraneoplastic encephalomyelitis (PEM). Paraneoplastic limbic encephalopathy (PLE) can occur as an isolated syndrome or as PEM with involvement of other parts of the nervous system (i.e., brainstem, cerebellum, peripheral nerves). The most common symptoms are a subacute amnestic syndrome, presenting as problems with short-term anterograde memory or more variable retrograde amnesia. Depression, personality changes, anxiety and emotional lability often precede the cognitive dysfunction. Seizures are common.[52, 53] PNDs occur in patients with a known diagnosis of a cancer or may precede the detection of the cancer by weeks, months or rarely a few years. In patients without a known cancer diagnosis, various signs or symptoms may suggest a PEM or PLE, including: subacute development of multifocal neurologic symptoms, CSF evidence of inflammation, elevated tumor markers (e.g., CEA, CA-125, PSA, etc…), a family history of cancer, unexplained anorexia or weight loss or other symptoms suggestive of cancer, and the presence of certain paraneoplastic antibodies in the serum and/or CSF. [52, 53]

The most common tumors associated with PLE are small cell lung cancer (SCLC) (75% of cases), germ-cell tumors (ovarian or testicular), thymoma, Hodgkin's lymphoma and breast cancer. [52, 53], while the most common antibodies associated with PLE are anti-Hu (ANNA-1), Anti-Ma2 (also called Anti-Ta; antigen is Ma2), CV2 (Anti-CMRP-5), Yo (PCA-1), and probably anti-neuropil. [52, 54-56] Anti-Hu antibodies are found in 50% of cases of PLE cases with SCLC. Identification of anti-neural antibodies is highly suggestive of an underlying neoplasm. Furthermore, the type of autoantibody may suggest the tumor type rather than the neurological syndrome. [52, 57] Almost one-third of patients with a neurological syndrome and autoantibodies will have more than one auto-antibody.[57, 58] In PLE associated with anti-Ma2 (Ta) antibodies and testicular cancer, about half of patients have dramatic improvement of their neurologic syndrome after treatment of their cancer. [56, 59]. This may be in part due to the ability to remove all the cancer through orchiectomy.[60] Hypothalamic involvement is common in patients with anti-Ma2 antibodies.[56] Antibodies to CRMP-5 (Anti-CV2 or Anti-CRMP-5), a protein in the collapsin response-mediator protein family are often associated with PNDs, including PLE. Peripheral neuropathy (47%) and autonomic neuropathy (31%) are the most common neurological signs. Subacute dementia and cerebellar ataxia each occur in about ¼ of patients, followed by neuromuscular junction disorders (12%), chorea (11%) and cranial neuropathy (17%, including optic neuropathy and loss of taste. Spinal fluid is often inflammatory. Anti-CV2 is most often seen with small-cell lung cancers, followed by thymomas. [61, 62] FLAIR MRI in Anti-CV2 antibody syndrome often shows caudate, anterior putamen with or without medial temporal lobe hyperintensity,[58] although thalamic T2-weighted hyperintensity can also occur (manuscript submitted). The striatal and thalamic involvement can appear similar to findings in CJD, however, unlike CJD the T2-weighted hyperintensity may extend beyond the deep grey nuclei into adjacent white matter and there are no diffusion-weighted abnormalities. Most patients with limbic encephalopathy and thymoma (often anti-CV2 or anti-VGKC antibodies) have significant neurologic improvement following tumor removal and treatment. [63] Table 13.3 summarizes some of the major antibodies, with their clinical phenotypes, that are associated with limbic encephalopathy.

Recently, there has been increasing awareness of several immune-mediated encephalopathies that are not always associated with cancers.[54, 64] In some of these syndromes, antibodies, and sometimes their antigens, have been identified. Two such syndromes of limbic encephalopathy are due to anti-voltage-gated potassium channels antibodies (VGKC) and to anti-neuropil antibodies. Patients with anti-VGKC antibodies present along a spectrum of nervous system involvement, from the peripheral to the central nervous system. Involvement of the peripheral nervous system alone may manifest as neuromyotonia (Isaac's Syndrome). Isolated CNS involvement may present as a seizure disorder or limbic encephalopathy.[54, 65-69] However, combinations of peripheral and central involvement, such as in Morvan's syndrome also occur. Some of these patients have limbic encephalopathy in isolation, while others have been shown also to exhibit different degrees of Morvan's fibrillary chorea, a syndrome characterized by neuromyotonia, myalgias, hyperhydrosis, and disordered sleep. [70] Anti-GAD antibodies, although commonly associated with stiff person syndrome, can also cause subacute ataxia, sometimes with mild cognitive complaints.[71] Novel antibodies against components of the CNS are continually being identified.[54] If autoimmune syndrome is strongly suspected, due to CSF or serological findings, concurrent or family history of autoimmune disorders, one should have a low threshold for sending serum and CSF to a research laboratory that specializes in identifying such antibodies.

Hashimoto's encephalopathy (HE) is a rare but probably under-diagnosed, treatable autoimmune disorder associated with chronic lymphocytic Hashimoto's thyroiditis [72, 73]. Often, it begins with a prodrome of depression, personality change or psychosis and progresses into a cognitive decline associated with myoclonus, ataxia, pyramidal and extrapyramidal signs, stroke-like episodes, altered levels of consciousness, confusion and/or seizures. Hallucinations or other psychoses are common. [72-74]. It is often confused with CJD because of their overlapping clinical profile. [5, 74]. Compared to CJD, HE is more frequently is associated with seizures and tends to have a more fluctuating course [74]. For unclear reasons, more women (85%) than men have been diagnosed with HE [74]. Patients may be euthyroid, hypothyroid, and even hyperthyroid, although the diagnosis cannot be made until a patient is euthyroid [74]. Elevated levels of either anti-thyroglobulin or anti-thyroperoxidase (anti-TPO) and neurologic and psychiatric symptoms when patients are euthyroid, in the absence of other possible etiologies suggest the diagnosis. The EEG frequently shows nonspecific abnormalities with asynchronous background slowing and intermittent diffuse or focal slow activity; however, as in CJD, triphasic waves or periodic sharp waves may occur [72, 75]. MRI is not specific but commonly shows increased T2-weighted subcortical, mesial-temporal or white matter signal, which may disappear after treatment [72, 76-78]. CSF often has increased protein, a non-specific finding that occurs in many other RPDs, including CJD [13, 72, 73]. The etiology of HE but may be due to the presence of a shared antigen in the brain and thyroid [72, 73, 79]. More than 90% of patients respond favorably to immunosuppression, typically high dose steroids followed by a long, slow taper, although some patients may have persistent symptoms or a fluctuating course [72, 75, 80]. Plasmapharesis may also be helpful [81].

Many other autoimmune disorders present as RPDs, and are important to consider because of potential for reversibility with immunosuppression. A new clinicopathologic entity called “cerebral amyloid inflammatory vasculopathy” recently has been described. These patients show acute or rapid onset of dementia. MRI shows evidence of amyloid-related hemorrhages and sometime large confluent white matter hyperintensities. Brain biopsy revealed Aβ amyloid cerebral angiopathy associated with chronic non-granulomatous vasculitis. With a single dose of dexamethasone, a patient made a rapid and nearly complete recovery over a few months.[82]

Collagen vascular and granulomatous diseases also affect the CNS through mechanisms other than vasculitis. Several of these disorders may cause an encephalopathy or rapidly progressive dementia, including primary angiitis of the CNS (PACNS), polyarteritis nodosa (PAN), sarcoidosis, systemic lupus erythematosus (SLE), Sjögren's syndrome, celiac disease (Sprue), Behçet's disease, and hypereosinophilic syndrome. [83-89] Some authors group these encephalopathies of non-vasculitic origin under the term non-vasculitic autoimmune inflammatory meningoencephalopathies (NAIM); this group includes Hashimoto's and Sjogren's encephalopathies; which almost uniformly have abnormal EEGs and respond to high dose steroids. [90] The heralding features of the disorder may be neurological

Subacute and chronic opportunistic infections associated with HIV infection and other immunocompromised states must always be considered in the differential diagnosis of RPD. Cryptococcus and JC virus infections typically present with meningitis or progressive focal neurologic deficits respectively, however, they also can present with rapid progression of dementia. [104] CNS infection with Mycobacteria may present as an inflammatory meningitis. A recent case report identified an atypical acid fast bacillus, Mycobacterium neoaurum, by PCR in autopsy brain tissue from a patient with rapidly progressive dementia who was on low dose steroids. CSF cell count, mycobacterial culture, and Ziehl-Nielsen staining all failed to demonstrate the presence of mycobacterium. It is possible that many undiagnosed RPDs could be caused by infectious organisms that escape detection using standard microbiological techniques. [9, 105, 106]. (For a review on diagnosis and etiology of encephalitis see Glaser et al 2006).

Spirochete infections are unusual causes of cognitive impairment, but important to consider as they are treatable. No workup for dementia, including RPD, is complete without an evaluation for CNS infection with Treponema pallidum, or “neurosyphilis.” Cognitive dysfunction is the most common neurological syndrome, although usually a late complication, of syphilis[107]. It occasionally presents with rapid progression, particularly in immunocompromised patients. [108] Serological testing with RPR and VDRL and CSF VDRL suggest the diagnosis. The CSF in neurosyphilis usually shows a pleiocytosis and an elevated protein. [107] Lyme disease is a systemic infection with the spirochette, Borrelia burgdorferi, which is transmitted to people from a tick bite. Neurological manifestations are rare in Lyme disease, but can include cranial nerve palsy, meningitis, polyradiculopathy, depression, psychosis, and dementia.[109] Although rapidly progressive dementia caused by Lyme disease has been reported, it is rare, [110, 111] but it is important to consider because it responds readily to treatment. [112]

Subacute sclerosing panencephalitis (SSPE) is a chronic CNS infection from the virus that causes measles and is still occurs in individuals from countries where measles infections are common. It typically occurs in children, but can occur in adults. [113]Patients develop progressive dementia, seizures (focal and/or generalized), myoclonus, ataxia, rigidity, and visual disturbances. In the late stage of the illness, patients are unresponsive, with spastic quadriparesis, brisk deep tendon reflexes and positive Babinski signs. EEG often reveals periodic slow-wave complexes with associated sharp waves every 3-10 seconds that are often temporally associated with myoclonus. Definitive diagnosis is made with elevated antibody titers to the measles virus in the blood and CSF in the appropriate clinical setting. [114]

PCNSL is an extranodal form of non-Hodgkin's lymphoma. It typically presents with symptoms of intracranial mass lesions, such as headaches, seizures, and focal neurological deficits, but can present as a rapidly progressive dementia.[121] A diffusely infiltrating PCNSL, sometimes called lymphomatosis cerebri, also occurs.[122] Symptoms of PCNSL include personality changes, irritability, memory loss, lethargy, confusion, disorientation, psychosis, dysphasia, ataxia, gait disorder, and myoclonus. [121-124] CNS lymphoma can mimic CJD. [5, 96, 125] PCNSL accounts for 2-3% of all CNS neoplasms. The vast majority of PCNSL are non-Hodgkin diffuse large B-cell type, but T-cell, Burkitt's and poorly characterized forms also occur.[121, 126] The incidence increased from the mid-1970s to the mid-1980s due to an escalating number of immunocompromised patients from transplants, chemotherapy, and patients with HIV before the era of HAART, but seems to have stabilized over the past decade. [126] We focus here on PCNSL in immunocompetent individuals. PCNSL occurs most commonly in the 6^th to 7^th decades, but can occur at any age, with a slight male predominance. [123]. Uveitis or vitreitisis present in about 10% of cases, preceding the tumor sometimes by months, in about 75% of cases; identifying the uveitis or vitreitis may allow earlier diagnosis of the cancer.[127]. In immunocompetent individuals, brain MRI may show isointense to mildly hyperintense T2-weighted signal consistent with mass lesions with minimal to moderate edema, often involving the cerebral hemispheres, basal ganglia, periventricular white matter, or corpus callosum. Lesions may be isolated or multiple and generally show contrast enhancement.[128] When presenting as lymphomatosis cerebri, imaging reveals progressive, diffuse white matter signal abnormality without significant (or any) enhancement or mass effect – likely from a diffusely infiltrative process without interruption of the blood-brain barrier. [122, 123] CSF can show a lymphocytosis, increased protein, and low glucose. Serial CSF cytologic evaluations are typically required to identify the lymphoma.[126] EEG may show symmetric or asymmetric nonspecific diffuse slowing [122, 123]Unfortunately, definitive diagnosis often requires brain biopsy. In cases of ocular involvement, diagnosis can sometimes be made by vitrectomy. When possible, it is important to avoid giving corticosteroids prior to biopsy, as steroids can cause tumor cell necrosis, resulting in temporarily shrinkage of the tumor, but preventing tissue diagnosis.[96, 126] Prognosis is poor with patients surviving only a median of 4 months or less without treatment, 12-18 months with whole-brain radiation therapy (WBRT) alone, however upwards of 40 or more months with a combination of aggressive chemo and radiotherapy. Chemotherapy includes high dose systemic methotrexate. The use of chemotherapy alone versus chemotherapy plus WBRT is controversial. Due to the increased risk of neurotoxicity, WBRT in patients over 60 is not recommended. Neurotoxicity presents as an RPD with dementia, ataxia and incontinence, with median onset just over one year post-WBRT [126, 129]

Intravascular lymphoma can occur in almost any organ, but commonly has one of four presentations: CNS, skin, hemophagocytic or fever of unknown origin. It is caused by the proliferation of clonal lymphocytes within blood vessels, with relative sparing of parenchyma.[130] The more acute form of CNS intravascular lymphoma typically presents in middle age as an acute or subacute dementia, often with transient ischemic attacks or strokes. Systemic symptoms (e.g., fever and weight loss) may be present. The tumor cells are thought to be activated or transformed lymphocytes and are typically an angiotropic large B cell lymphoma, although cell-type forms also occur. These clonal lymphocytes preferentially bind endothelium. Imaging in CNS intravascular lymphoma is variable. MRI may show multiple areas of T2-weighted hyperintensity with patchy enhancement on T1-weighting, with or without edema. [131] Unfortunately most cases reported in the literature were diagnosed post-mortem; therefore a high index of suspicion, and a low threshold for brain biopsy, is required for patients with a rapidly progressive dementia and focal T2-weighted abnormalities on MRI. [99, 127, 132] Laboratory findings can include elevated ESR, serum lactate dehydrogenase, CSF pleiocytosis and increased protein. [132, 133] Survival in intravascular lymphoma is usually poor, especially without treatment. Aggressive treatment is needed for both PCNSL and intravascular lymphoma. The combination of chemo- and radiotherapy is better than radiotherapy alone. [127, 130, 132]

Adult presentations of metabolic disorders that typically afflict children can in rare instances also present as dementia in the adult. These dementias are usually associated with a constellation of symptoms such as weakness, spasticity, and ataxia and tend to be more slowly progressive. They can present with rapid cognitive decline. In the proper clinical context, of gastrointestinal disturbance, fluctuating course, an unexplained pain syndrome, and/or worsening after use of new medicines, porphyria should be ruled out. Adult onset metachromatic leukodystrophy (MLD) presented as an RPD in a woman who developed psychiatric symptoms and severe cognitive decline over 18 months with no weakness or ataxia.[143] Other leukodystrophies can also present as RPD. Orthochromatic leukodystrophies (OLD) are a heterogeneous group of metabolic disorders in which the specific enzymatic defects have not been found. Most are sporadic, but dominant inheritance has been reported. One report described 2 family members (57 and 38 at presentation) with a dominantly-inherited OLD who developed rapid dementia progressing to death over 2-3 years.[144] Finally, Kuf's disease, the rare adult form of Neuronal Ceroid Lipofuscinoses (NCLs), can present as RPD. Kuf's is an autosomal recessive lysosomal storage disease in which acid phosphatase staining ceroid and lipofuscins accumulate in neurons, causing a progressive encephalopathy. Kuf's disease typically presents in early adulthood. Type A Kuf's patients present with a progressive myoclonic epilepsy, while type B patients present with dementia which often begins with psychosis. A case reported in 1997 involved a 49 year old woman who initially presented with alternating catatonia and acute psychosis over 5 months before the development of dementia over the next 2 months. Diagnosis was made by acid phosphatase staining of brain and skin biopsies.[145] We recently diagnosed a 50 year old woman with a methylmalonic (and malonic) academia (MMA) who had developed significant cognitive impairment after a several month prodrome of gastrointestinal disturbance and psychiatric disturbance. She had low normal vitamin B12 levels and normal homocysteine. Despite thorough evaluation of her vitamin B12 pathways, the cause of her metabolic disorder is still unknown. (M. Geschwind, unpublished data)

Several toxins can cause an RPD. Exposure to heavy metals, such as arsenic, mercury, aluminum, lithium, lead can lead to cognitive decline, particularly following acute exposure. However, most cases of acute exposures result in florid encephalopathies that progress over hours to days and thus would not be confused with rapidly progressive dementias which progress over weeks to months. Manganese toxicity, found usually in miners, can present with significant parkinsonism. [138]