Presenile Dementia Mary Ellen Quiceno M D Case

Presenile Dementia Mary Ellen Quiceno, M. D.

Case #1 n n n n 33 y. o. reported memory loss in 2000. In 2002, episodes of left-sided numbness & weakness. Febrile day prior to first admission in 2002 for h/a, n/v, and left-sided weakness. Abnormal MRI and LP. Progressively worsened and developed seizures, tremor, startle, and ataxia. No family history. Died a week after brain biopsy from pulmonary embolism. Biopsy nondiagnostic.

MRI/MRA brain, spine. n n Subtle alteration of FLAIR signal in the basal ganglia bilaterally and subtle diffuse enhancement in the pons and thalami (nonspecific findings, ? occult vascular malformations capillary telangiectasias). No change on repeat brain scans done 12/02, 6/03. Developed atrophy. Normal MRA. C 2 T 2 hyperintensities (? myelomalacia or demyelinization).

Case #2 n n n Mid-40’s Caucasian man with degenerative dementia. Institutionalized. Parents deny history of dementia or psychiatric disturbances in family. Taking Haldol. Exam: No chorea. Very disinhibited. Difficult to examine repeatedly says “I love you”.

Case #2 Diagnosis Once Haldol stopped, chorea was seen. n Family finally disclosed that patient was adopted and HIS family history was unknown. n Tested positive for Huntington’s disease. n

Presenile Dementia

Presenile Dementia Rare <40 years old. n Overall prevalence of presenile dementias in the 45 to 65 year old age group 1580/100, 000. n

Presenile Dementia n Age of onset and premorbid functioning. ¨ <65 y. o. ¨ Psychiatric history? Education? Level of functioning? n n Family history. Clinical characteristics. ¨ Neurological n dysfunction. Other diseases or dysfunction (medical, psychiatric).

Expected Age-related Cognitive Changes Bradyphrenia. n Trouble with recall of names of people/places. n Decreased concentration. n Language, vocabulary spared and may improve. n

Why Age of Onset Matters n Metabolic & genetic: very early. ¨ Can have later onset of some metabolic d/o. Anticipation with triplicate disorders. n Differential differs between presenile and senile dementias. n Some disorders have more predictable onset. n

Temporal Course of Disease Slowly or rapidly progressive? n Gradual and insidious, stepwise, fluctuating, acute onset then static? n

Cognitive Profile Onset with memory, frontal executive dysfunction, other… n Cortical. n ¨ Language, ¨ AD, n memory, praxis. FTD. Frontal-subcortical. ¨ Slow, poor attention, decreased verbal output, apathy. ¨ Other dementias. n Mixed.

Associated Features Behavioral & Neurological Personality & behavior changes. n Depression & psychosis. n Seizures. n Myoclonus. n Ataxia. n Tremor. n Parkinsonism. n

Differential Diagnosis

Differential Diagnoses n Neurodegenerative disorders. ¨ n n Vascular. Infectious. ¨ n n Anti-Yo. Autoimmune & Inflammatory. ¨ n Syphilis, CJD, v. CJD, HIV-related. Tumor & Paraneoplastic disease. ¨ n SCA, HD, DRPLA, Alzheimer’s disease, FTD, DLB & related dementias. MS, sarcoid. Trauma. Toxic & Metabolic.

Inherited Dementias n n n n AD FTD HD SCA Wilson’s Prion CADASIL n Storage Disorders ¨ Lysosomal n n Niemann-Pick MLD ¨ Peroxisomal n ALD ¨ Lafora Body Disease ¨ Mitochondrial d/o

Rapidly Progressive Dementias n Reversible n Irreversible ¨ NCSE ¨ CJD ¨ Drugs ¨ Rapidly ¨ Meningitis ¨ Whipple’s ¨ Tumor progressive variants of AD

Dementia-Plus Syndromes n Cognitive impairment in the setting of more wide-spread neurological disturbance. ¨ Ataxia: HD, DRPLA, Wilson’s, SCA, Prion ¨ EPS: FTDP-17, HD, Wilson’s ¨ Psychiatric: FTD, HD, Wilson’s

More Common Dementias

Most Common Senile & Presenile Dementias n SENILE ¨ Alzheimer’s ds. 70 -80%? ¨ Lewy Body ds. ¨ Vascular ds. ¨ FTD. ¨ Other. n PRESENILE ¨ Alzheimer’s ds 30% ¨ Vascular ds 15% ¨ FTD 13% ¨ LBD 4% ¨ Other 25% n HD, MS, CBGD, Prion disease, PD.

Alzheimer’s disease May manifest in 4 th decade. n Autosomal dominant with complete penetrance. n Presenilin 1 on chromosome 14. n ¨ APP on chr. 21 (Down’s), PS-2 on chr. 1 ¨ Creates abnormally aggregated b-amyloid

Neuropathology the same in Presenile and Senile Onset AD n Neuritic plaques ¨ extracellular ¨ b-amyloid n Neurofibrillary tangles ¨ intracellular ¨ tau n protein Basal forebrain nuclei ¨ leads to Ach deficit

Clinically Similar n Early involvement of medial temporal lobe. ¨ hippocampus and entorhinal cortex n n n Parietal lobe dysfunction. Myoclonus may be more prominent in familiar forms. Naming may be spared until late in familiar forms.

Frontotemporal Lobar Degenerations (FTLD) Onset 20 -75 years of age. n Male predominance. n Half have family history (may be heterogeneous). n Various genetic mutations known. n ¨ Chr. 17 tau gene mutation most common. FTD with parkinsonism. n Clinically variable within families. n

FTLD types n Pick’s disease. ¨ 3 repeat tau isoform aggregates FTD: behavioral, PPA, SD. n CBGD. n FTD associated with MND. n ¨ Ubiquitin positive, tau negative inclusions

FTD n Behavioral Onset attributed to depression, referred to psychiatrist. ¨ Personality change, blunted affect, loss of motivation. ¨ Frontal atrophy on MRI (may be missed). n ¨ First Semantic Dementia ¨ Progressive fluent aphasia. ¨ Mistaken for AD. n Progressive Aphasia ¨ Non-fluent aphasia. ¨ Paraphasic errors. ¨ Orofacial apraxia.

FTD

Vascular Dementia Usual risk factors, plus unusual cardiac, hematological, metabolic, and genetic causes. n CADASIL (cerebral autosomal dominant arteriopathy with n subcortical infracts and leukoencephalopathy). ¨ Mean age of presentation in 50 -60’s. ¨ Can present in 20’s with migraines w/aura and MRI changes. n Consider MRI in migraineurs w/ atypical auras, family hx. ¨ Chr. 19 mutation on Notch 3 gene

CADASIL Cerebral non-atherosclerotic, nonamyloid angiopathy of white matter and basal ganglia n Stroke 84%, dementia 80%, migraine with aura or mood disorders in 20% n Slow stepwise deterioration of cognitive and neurological function n ¨ Frontal dysfunction, pseudobulbar palsy, gait problems, incontinence

MRI in 2 patients with CADASIL n n The top MRIs are from a 30 year-old with migraine w/aura and CADASIL The bottom MRIs are from a 57 year-old with migraine, stroke, and dementia.

Lewy Body Dementia Rare in presenile populations. n Dementia. n Fluctuating cognitive impairment or consciousness. n Visual hallucinations. n Parkinsonism. n Neuritic plaques and Lewy bodies n ¨ a-synuclein inclusions

Transmissible Spongiform Encephalopathies (Prion) Diffuse brain spongiosis. n Deposition of abnormal Pr. P (prion protein). n 90% sporadic, others acquired or inherited. n ¨ Post-translational conversion of the native prion protein in sporadic forms, causing accumulation in neurons. ¨ Mutations to PRNP gene on chr. 20 in inherited cases.

Sporadic & Inherited Prion D/Os n n CJD incidence 1/1, 000(? ) nv. CJD = BSE ¨ Genetic susceptibility in 40% of UK residents n n Rapid dementia in 60’s w/death <6 mo. Insomnia, amotivation, myoclonus, ataxia, cortical blindness. n Familial CJD ¨ similar n to sporadic Fatal Familial Insomnia ¨ insomnia & dysautonomia n Gerstmann-Straussler -Scheinker syndrome ¨ ataxia, dementia

Hyperintensity in the basal ganglia and cortical ribboning are distinct imaging features of sporadic CJD.

MRI differences in CJD, nv. CJD MRI of nv. CJD patients is associated with hyperintensity of the pulvinar (posterior nuclei) of the thalamus n MRI of sporadic CJD is associated with high signal changes in the putamen and caudate head. n

Summary Alzheimer’s disease n Vascular dementia n FTLD n Prion disorders n

Less Common Dementias

Wilson’s Disease Autosomal recessive disorder of copper transport n Prevalence of 1/50, 000 in UK. n Tremor, dystonia, chorea, ataxia, dysarthria, psychiatric & cognitive changes. n Low serum copper and ceruloplasim levels with increased 24 o urinary Cu excretion. n

Huntington’s Disease n Family history may NOT be known. ¨ Suicide, institutionalization. ¨ Chorea may be suppressed by antipsychotics used by psychiatrist. n Trinucleotide repeat (CAG) >35 on chr. 4 ¨ AD with complete penetrance. ¨ Sporadic mutations rare. 25, 000 affected in US. 10/100, 000 prev. n Caudate atrophy seen on MRI. n

Huntington’s Disease

Whipple’s Disease n Caused by bacteria: Tropheryma whippelii n Classic clinical features ¨ chronic diarrhea with malabsorption, abdominal pain, relapsingremitting migratory polyarthralgia, lymphadenopathy, weight loss, hyperpigmentation of the skin, and fever of unknown origin. CNS may be affected in 40%. n Neurological presentation is rare (5%) and is often followed by disease confined to the CNS. n

Neuropathology of CNS Whipple’s Disease Disseminated or focal macrophagic encephalitis or meningoencephalitis favoring subpial and subependymal grey matter. n Mass lesions and obstructive hydrocephalus can be found. n Infarcts are also described. n ¨ secondary to surrounding chronic inflammation or to a primary vasculitic process

Symptoms of CNS Whipple’s Ds n n n Cognitive changes (71%), Supranuclear gaze palsy, Altered consciousness are the commonest neurological findings. n n n n Oculomasticatory (OMM) and oculofacial skeletal myorhythmia (OFSM), Myoclonus, Ataxia, Hypothalamic dysfunction, Cranial nerve abnormalities, UMN dysfunction, Sensory deficits.

Myorhythmia n Pathognomonic for Whipple's disease n Oculomasticatory: Slow, smooth convergentdivergent pendular nystagmus associated with synchronous contractions of the jaw. n Oculo-facial-skeletal: nystagmus plus synchronous contractions of other body parts. n Occur in 20% and are always associated with a supranuclear vertical gaze palsy.

Guidelines for the diagnosis of CNS Whipple’s Disease n Definite diagnosis ¨ presence of OMM or OFSM or a positive biopsy or positive PCR analysis. ¨ Neurological signs are required when the positive results have been obtained from non. CNS tissue.

CNS Whipple’s Disease n The majority of intestinal (70%), brain (83%), lymph node and vitreous fluid biopsies (89%) performed are diagnostic. ¨ Electron microscopy ¨ T whippelii DNA is found in normals. ¨ The analysis of preferably more than one tissue substrate have been advised to maximize sensitivity and specificity. n PCR may also be useful to monitor response to treatment and prognosis.

Testing for Whipple’s n PCR in CSF can be negative in 20 -30%. ¨ 80% with neurological symptoms and 70% of patients without neurological symptoms have yielded positive CSF PCR results in one series. CSF PCR may be more sensitive in the presence of CSF pleocytosis. n ESR, CSF & serum ACE concentrations may be elevated. n

Treatment of Whipple’s Disease n Ceftriaxone 2 g IV× 3/day plus ampicillin 2 g IV × 3/day for 14 days ¨ Followed by oral TMP-SMX (160+800 mg) twice daily for 1 -2 years n Ceftriaxone 2 g IV BID plus streptomycin 1 g/day for 14 days ¨ Followed by oral TMP-SMX (160+800 mg) twice daily for 1 -2 years or cefixime 400 mg po qd for 1 -2 years

DRPLA (Dentatorubral-Pallidoluysian Atrophy) n Ataxia, choreoathetosis, dementia, and psychiatric disturbance. n Positive family hx (AD) and the detection of a CAG repeat (48 -93) on chr. 12. n Significant anticipation: 28 yrs/gen w/ paternal transmission and 15 yrs/gen w/ maternal transmission. n Age of onset is from 1 to 62 years with a mean age of onset of 30 years.

DRPLA Described in Japanese and African American families. n Differential: HD and SCA 1, 2, 3, 6, 7. n n The history of ataxia as an early symptom as well as atrophy of the cerebellum and brainstem (particularly pontine tegmentum) on imaging study is important in the differential diagnosis.

Spinocerebellar Ataxias (SCA) n Slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. n Atrophy of the cerebellum. n The hereditary ataxias are categorized by mode of inheritance, gene, or chromosome locus.

Spinocerebellar Ataxias 26 described. n Triplicate repeats in 1, 2, 3, 6, 7, 8, 10, 12, & 17. n Difficult to distinguish clinically. n ¨ Some have peripheral neuropathy, seizure, dementia associated n Genetic testing available for some SCAs.

World-wide Incidence of SCAs

SCA 3 or Machado-Joseph disease n The diagnosis of SCA 3 is suggested in individuals with the following findings ¨ Cerebellar ataxia and pyramidal signs (type II disease) associated in variable degree with a dystonic -rigid extrapyramidal syndrome (type I disease) ¨ Or peripheral amyotrophy (type III disease) n n Minor (but more specific) clinical signs such as progressive external ophthalmoplegia, dystonia, action-induced facial and lingual fasciculationlike movements, and bulging eyes Autosomal dominant inheritance

Differential Diagnosis of Ataxias ¨ multiple sclerosis, ¨ ataxia-telangiectasia, ¨ vascular ¨ alcoholism, ¨ primary ¨ vitamin deficiency (E), ¨ Friedreich’s ataxia, disease, or metastatic tumors, ¨ or paraneoplastic diseases associated with occult carcinoma of the ovary, breast, or lung.

Paraneoplastic Limbic Encephalitis (PLE) n Represents an autoimmune response to tumor antigens ¨ Predominantly Neuronal nuclear (Anti-Hu) ab (50% of cases) ¨ Lymphocytic infiltrate in CNS n Can precede cancer diagnosis ¨ small n cell lung cancer (80%), testicular, breast Symptoms usually progress over the course of weeks to months, reaching a plateau of neurologic disability.

Symptoms of PLE · Memory loss, personality changes, anxiety or depression, neuropsychiatric disturbances, partial or generalized seizures, olfactory and gustatory hallucinations, sleep disturbances, and abnormalities in other homeostatic functions. · Focal neurologic disturbances such as aphasia, weakness, or numbness. · Brainstem encephalitis · Autonomic dysfunction in 1/4. · Motor neuron dysfunction. · Lambert-Eaton myasthenic syndrome occurs in 1016% of cases.

Symptoms of PLE · Subacute Sensory Neuronopathy · · Seen in 70 -80% of cases. Symptoms include asymmetric focal numbness or paresthesias, typically involving the face, trunk, and proximal extremities. · burning or lancinating dysesthesias of all extremities may be noted at later stages. ·

Diagnosis of PLE n Serum and CSF paraneoplastic antibody panel ¨ n Anti-Hu or other PEM antibodies (anti-CV 2, anti-Yo, anti-Ma 1, anti-Ta or anti-Ma 2) may be found. Cerebrospinal fluid · Cell count, protein, glucose, oligoclonal bands, Ig. G synthesis rate, cytology, and PCR for herpes simplex virus and varicella zoster virus n Evaluate for an underlying malignancy & Serum tumor markers n Brain MRI may help to rule out the differential diagnoses. Usually, MRI in a patient with PEM is unremarkable, although T 2 -weighted hyperintensity may be noted in mesial temporal lobes and associated limbic structures.

Mesial temporal hyperintensity demonstrated on T 2 -weighted (left) and fluid-attenuated inversion recovery (FLAIR, right) MRI

Treatment of Paraneoplastic Limbic Encephalitis Plasmapheresis n IVIG n Steroids or Cytoxan n Monitor for cancer n

Steroid-responsive Encephalopathies Heterogeneous group of disorders n May represent underlying cerebral vasculitis n Circulating autoantibodies n n Hashimoto’s Encephalopathy

Hashimoto’s Encephalopathy n n n Seizures, stroke-like events, temporary neurologic deficits, and a variety of psychiatric disturbances from dementia to visual hallucinations and frank psychosis. Significantly elevated antithyroid antibody titers, mainly anti-thyroid peroxidase (TPO) antibodies. Pathogenetic hypotheses proposed so far ¨ excessive thyrotropin-releasing hormone output, ¨ edema-induced cerebral dysfunction, ¨ global hypoperfusion, ¨ an autoimmune-mediated inflammatory attack of cerebral vessels.

Approach to Diagnosis of Presenile Dementia

Approach to Diagnosis Observation n History from family n Explore different cognitive domains & impact on daily functioning n Psychiatric history n Family history n Physical and neuropsychological exams n

Investigations for Determination of Diagnosis and Recognition of Treatable Disorders n n n Blood & Urine testing Drug screen TSH, B 12, ? ESR Syphilis Vasculitides/CTD HIV, heavy metals, Cu/ceruloplasm n n EEG MRI brain Possible LP Possible brain or tissue biopsy ¨ CADASIL, vasculitis, Whipple’s, CJD n Other. . .

Treatable Causes of Cognitive Impairment n Don’t forget these: ¨ Obstructive Sleep Apnea ¨ Depression ¨ Drugs & alcohol (thiamine deficiency, Li toxicity, BZD) ¨ Epilepsy

Treatment Accurate diagnosis extremely important n Supportive care for patient and family n Treat psychiatric symptoms n Acetylcholinesterase inhibitors and NMDA receptor antagonist n Anti-epileptics n