Table 3. Reversible forms of young-onset dementia.

Disorder	Pathogenesis	Clinical Features in addition to Cognitive Dysfunction	Specific Diagnostic Studies with Suggested Order of Testing	Interventions in addition to Supportive Care
Inflammatory
Multiple sclerosis124,128-132	Sporadic	Age of onset is 20-40 years; more common in females; may be relapsing/remitting, primary progressive, progressive relapsing, or secondary progressive and present with sensory disturbance of limbs, partial or complete vision loss, motor dysfunction of limbs, diplopia, and ataxia	MRI (enhancing and non-enhancing lesions in brain and/or spinal cord white matter with characteristic perpendicularly oriented “Dawson's fingers” in the periventricular region); CSF (elevated oligoclonal bands and IgG index)	Corticosteroids for acute attack; other immunomodulatory agents for long-term therapy
Neurosarcoidosis125	Sporadic	Cranial mononeuropathy (esp CN V, II, VIII), neuroendocrine dysfunction, myelopathy, hydrocephalus, aseptic meningitis, peripheral neuropathy, myopathy, multi-focal neurological deficts	MRI (meningeal or parenchymal enhancement, parenchymal nodules); CSF (elevated opening pressure, normal or low glucose, mononuclear pleocytosis, incr IgG, oligoclonal bands, elevated ACE level); chest CT for lung or lymph node involvement; biopsy for noncaseating granuloma	Corticosteroids for acute symptoms, other immunomodulatory agents for long-term therapy
Paraneoplastic and Autoimmune Limbic encephalitis126,127,133	Associated with multiple antibodies +/− occult or known malignancy	Acute/subacute changes in mood and behavior change, complex-partial seizures	MRI (T2 sequence with hyperintensity or contrast enhancement in medial temporal lobes); CSF (elevated protein); EEG (focal or generalized slowing or epileptiform activity in temporal region); paraneoplastic and autoimmune antibody testing on serum +/− CSF	Immunosuppression with high dose corticosteroids acutely, treat underlying tumor, chronic therapy may require long-term immunomodulatory agents
Infectious
HIV dementia134,139	HIV infection with consequent immune activation of microglia	Psychomotor slowing, mood lability	MRI (cerebral atrophy especially in basal ganglia and frontal white matter); blood tests (low CD4 count, high HIV viral load); CSF (rule out other opportunistic causes)	HAART therapy treats HIV infection to reduce dementia risk
Neurosyphilis135,138,142	Treponema pallidum	Personality change; meningitis, decr visual acuity, hearing loss, general paresis, tabes dorsalis	MRI (meningeal enhancement), blood tests (VDRL, FTA-ABS); CSF (VDRL, FTA-ABS, incr protein, lymphocyte pleocytosis)	Penicillin G, ceftriaxone if penicillin-allergic, doxycycline if resistant
Whipple disease136,141,143	Tropheryma whipplei	Migratory arthralgia, weight loss, GI symptoms, oculomasticatory myorhythmia, ataxia, endocarditis	MRI (variable depending on symptoms); CSF PCR of saliva or stool; upper endoscopy with small bowel biopsy (periodic acid-Schiff-positive macrophages in lamina propria)	Ceftriaxone or penicillin for initial therapy; TMP-SMX as maintenance therapy
Progressive multifocal leuko-encephalopathy137,140,144,145	Reactivation of JC virus in immunosuppressed patients	Hemianopia, hemiparesis or monoparesis, ataxia	MRI (multifocal non-enhancing lesions limited to white matter that do not conform to vascular territories without mass effect); CSF (PCR detection of JC virus); EEG (nonspecific diffuse slowing)	HAART and high-dose glocucorticoid therapy if coinfected with HIV; stop immunosuppression; cytarabine for pt with hematologic malignancy; not reversible
Toxins
Alcohol and other drugs of abuse (sedatives, inhalants, etc.)146,148	Ingestion with neurotoxic effects Alcohol-related dementias include thiamine deficiency, hepatic encephalopathy, and Marchiafava-Bignami disease	All drugs of abuse: ataxia, tremor, blurred vision, dysarthria, psychiatric symptoms, seizures, coma Sedative overdose: respiratory depression Inhalant overdose: respiratory distress, headache, arrhythmia	All drugs of abuse: urine and serum drug screen Thiamine deficiency: MRI (signal change or atrophy of anterior thalamus or mamillary bodies) Hepatic encephalopathy: MRI (T1 hyperintensity in globus pallidus) Marchiafava-Bignami disease: MRI (signal change in the corpus callosum) Chronic alcohol use: MRI (atrophy in cerebellar vermis> hemispheres)	Cessation of offending agent Alcohol overdose: IVthiamine before glucose Sedative overdose: flumazenil
Heavy metal poisoning147	Occupation/environmental exposures	Mercury poisoning: psychiatric symptoms, distal sensory and motor neuropathy, GI symptoms, weakness, developmental delay, inflammation of gums, constricted visual fields, deafness, ataxia Arsenic poisoning: arrhythmia and ARDS Lead poisoning: anemia	Mercury poisoning: mercury level in blood >100 mcg/L and urine >100 mcg/L Arsenic poisoning: arsenic level in urine >50 mcg/L Lead poisoning: lead level in blood >25 mcg/dL; NCS	Avoid exposure; chelation
Metabolic encephalopathy149-153	Hepatic encephalopathy: excess ammonia Renal failure or dialysis disequilibrium syndrome: uremia Hyponatremia Hypernatremia	All: weakness, agitation, fluctuating cognition and behavior, seizures, coma	All: blood tests (comprehensive metabolic panel, ammonia); MRI of brain primarily to exclude other Diagnoses Hepatic encephalopathy: MRI (T1 hyperintensity in globus pallidus)	All: treat underlying cause Hepatic encephalopathy: lactulose and rifaximin Uremia: dialysis Hyponatremia: correct slowly with IVF to avoid central pontine myelinolysis
Wilson's disease172-174	AR mutation in ATP7B on Chr13 inhibits copper metabolism	Psychiatric symptoms, liver disease, movement disorder or rigid dystonia, ataxia, Kayser-Fleischer rings on slit-lamp exam	Blood tests (low copper and ceruloplasmin); urine (increased copper excretion); liver biopsy (incr hepatic copper concentration); genetic testing	Penicillamine, trientine, zinc
Endocrinopathy
Glucose dysregulation (hypoglycemia, hyperglycemia)154	Hypoglycemia: insulin, alcohol, malnourishment, liver disease Hyperglycemia: diabetes esp type I with inadequate insulin or acute infection	Hypoglycemia: change in behavior with anxiety, visual changes, seizures, palpitations, diaphoresis, variable focal neurological deficits, perioral paresthesia around mouth Hyperglycemia: polyuria, polydipsia, GI symptoms, weakness, fatigue, shortness of breath, fruity breath	Hypoglycemia: blood tests (glucose <60 mg/dL, assess for associated metabolic derangements) Hyperglycemia: blood tests (glucose >200 mg/dL, assess for associated metabolic derangements)	Hypoglycemia: carbohydrates (15-20g oral glucose), glucagon injection, IV dextrose Hyperglycemia: IVF, insulin
Thyroid dysfunction (hypothyroidism, hyperthyroidism)155,156,161,164,167	Hypothyroidism: autoimmune thyroiditis, infiltrative disease, TSH orTRH deficiency Hyperthyroidism: Graves disease, multinodular goiter	Hypothyroidism: weakness, fatigue, cold intolerance, constipation, dry skin, weight gain, hoarseness, bradycardia, depression Hyperthyroidism: heat intolerance, anxiety/irritability, tremor, diaphoresis, diarrhea, weight loss, tachycardia, Graves ophthalmopathy	Blood tests for both (TSH, free T4, thyroid autoantibodies); MRI (to rule out other possibilities); thyroid ultrasound Hypothyroidism: EEG (slow background activity) Hyperthyroidism: EEG (epileptiform activity)	Hypothyroidism: levothyroxine Hyperthyroidism: radioactive iodine, antithyroid medications, beta blocker, or thyroidectomy
Parathyroid dysfunction (hypoparathyroidism, hyperparathyroidism)157,158,162,163	Hypoparathyroidism: radiation of head/neck, radioactive iodine, low calcium intake Hyperparathyroidism: parathyroid adenoma or hyperplasia, parathyroid carcinoma, ectopic PTH from non-parathyroid neoplasm, multiple genetic mutations	Hypoparathyroidism: weakness, fatigue, irritability/anxiety/depression, tetany, seizures, muscle cramps, papilledema, extrapyramidal symptoms Hyperparathyroidism: weakness, fatigue, bone pain, myalgia, depression, nephrolithiasis, osteoporosis	Blood tests for both (Ca, PTH, Phosphorus, Mg, creatinine, vitamin D, alkaline phosphatase); urinary calcium Hypoparathyroidism: CT (basal ganglia calcification) Hyperparathyroidism: bone mineral density, renal imaging	Hypoparathyroidism: calcium and vitamin D Hyperparathyroidism: avoid calcium in diet, saline hydration, calcitonin, bisphosphonates, glucocorticoids, dialysis
Addison's disease159,165,168	Primary adrenal insufficiency, autoimmune/infectious adrenalitis, metastatic cancer or lymphoma, adrenal hemorrhage or infarction, abrupt withdrawal from corticosteroids	GI symptoms, weakness, fatigue, lethargy, fever, systemic “shock” and coma, hyperpigmentation if primary adrenal insufficiency	Blood tests: 8 AM serum cortisol and plasma ACTH; ACTH stimulation test; basal ACTH, renin, aldosterone levels	IVF resuscitation, glucocorticoids (hydrocortisone, dexamethasone, prednisone, fludrocortisone), DHEA if glucocorticoids fail
Cushing's syndrome159,160,166	Cushing's disease (pituitary hypersecretion of ACTH), ectopic secretion of ACTH by nonpituitary tumors, ectopic secretion of CRH, adrenal adenoma or hyperplasia, exogenous glucocorticoids	Central obesity, moon facies, supraclavicular fat pads, skin atrophy, purple striae, proximal muscle weakness, hirsutism, oligomenorrhea, impotence, obesity, hypertension, glucose intolerance	Late night salivary cortisol, urinary cortisol, low dose dexamethasone suppression test (2 of these must be abnormal); CT or MRI of adrenal glands or pituitary gland	Resection of ACTH- or cortisol-secreting tumor; pituitary irradiation; bilateral adrenalectomy; somatostatin analog for metastatic or ectopic ACTH-secreting tumor
Nutritional deficiency
B12169,171	pernicious anemia, gastrectomy/gastritis, strict vegans	megaloblastic anemia, jaundice, fatigue, atrophic glossitis, subacute combined degeneration (sensory and motor findings referable to spinal cord tracts), peripheral polyneuropathy	blood test (low B12 and folate, high homocysteine and methylmalonic acid, Ab to intrinsic factor); peripheral blood smear (macrocytic RBC, hypersegmented neutrophils); Schilling test; EMG and NCS; MRI spine (T2 hyperintensity of dorsal columns)	intramuscular B12 (1 mg every day for 1 week, then 1 mg every week for 4 weeks, then 1 mg every month until deficiency is reversed)
Thiamine (associated with Wernicke-Korsakoff syndrome)146	Malnourishment associated with chronic alcoholism, hyperemesis	Prominent anterograde memory deficits with confabulation, ataxia, ophthalmoplegia	Blood test (thiamine, RBC folate); MRI (signal abnormality or atrophy of medial thalamus, mamillary bodies, periaqueductal gray matter)	IV thiamine before glucose
Niacin (pellagra)170	Malnutrition associated with alcoholism or anorexia, carcinoid syndrome, prolonged use of isoniazid, Hartnup disease (defective amino acid transporter)	Dermatitis, diarrhea	Bloodwork (low niacin, tryptophan, NAD, NADP)	Niacin supplementation (25-300 mg by mouth daily)
Transient epileptic amnesia175	Unknown	More common in elderly; recurrent transient episodes of isolated anterograde memory loss, interictal memory difficulties	EEG (temporal lobe spikes); CT or MRI (atrophy of hippocampus)	Anticonvulsant therapy affects progression but does not completely reverse cognitive deficits
Obstructive sleep apnea176,178	Intermittent hypoxemia or sleep deprivation; Risk factors include obesity, large neck circumference, anatomically narrow airway	Snoring, snort arousals, morning headache, daytime somnolence, irregular respiratory patterns during sleep	Polysomnography with apneic pauses	Behavior modification (weight loss, change sleep position), positive airway pressure, oral devices, uvular and palatal surgery
Normal pressure hydrocephalus179	Impaired CSF flow; more common after head trauma, CNS infection, CNS hemorrhage	Gait disturbance (“magnetic”), urinary incontinence	MRI (ventriculomegaly, periventricular white matter hyperintensity, no evidence of CSF flow obstruction); high volume LP or CSF drain to identify patients that may respond to shunt placement	Ventriculoperitoneal shunt; cognitive deficits rarely reverse with this procedure although intervention may prevent further decline

Abbreviations: CSF = cerebrospinal fluid

LP = lumbar puncture

MRI = magnetic resonance imaging

EMG = electromyography

NCS = nerve conduction study

EEG = electroencephalography

PET = positron emission tomography

CT = computed tomography

EKG = electrocardiography

ACE = angiotensin converting enzyme

HIV = human immunodeficiency virus

HAART = highly active antiretroviral therapy

VDRL = venereal disease research laboratory

FTA-ABS = fluorescent treponemal antibody-absorption

PCR = polymerase chain reaction

ARDS = adult respiratory distress syndrome

IVF = intravenous fluids

TSH = thyroid-stimulating hormone

TRH = thyrotropin-releasing hormone

T4 = thyroxine

T3 = triiodothyronine

PTH = parathyroid hormone

ACTH = adrenocorticotropic hormone

DHEA = dehydroepiandrosterone

CRH = corticotropin-releasing hormone

Ab = antibody

NAD = nicotinamide adenine dinucleotide

NADP = nicotinamide adenine dinucleotide phosphate