Acute and subacute encephalopathy

Drugs and toxic encephalopathy: Exogenous causes account for 10% of dementias: alcohol and drugs (nitrous oxide, methotrexate, 5-fluorouracil/levamisole, clioquinol), intoxication (alcohol, barbiturates, sedatives, opiates), heavy metals (Pb) and hydrocarbons (solvents) and carbon monoxide.

Systemic diseases: Endogenous disorders causes are responsible for 5% of dementias. They include: liver, kidney or heart failure, hypoxia or carbon dioxide, severe anemia, excess or deficiency of thyroid, pituitary, adrenal or parathyroid hormone, electrolyte, acid-base, and metabolic disturbances (glucose, ketones, vitamins). Although a mitochondrial disorder for the sake of simplicity we will include subacute necrotizing encephalopathy (SNE) or Leigh disease: Several synonyms exist such as Leigh necrotizing encephalopathy, Leigh syndrome and necrotizing encephalomyelopathy of Leigh. Adult-onset forms of SNE are sporadic, or inherited in an autosomal recessive, autosomal dominant, X-linked, or mitochondrial trait. To complicate matters even more several different types of genetically determined enzyme defects can cause SNE. As with other mitochondrial disorders, the onset of neurologic symptoms present from the 1^st - 6^th decade with acute or subacute onset, often precipitated by surgical intervention or febrile illness. The disease can present with a variety of symptoms such as brainstem dysfunction (central respiratory failure, intermittent oculomotor palsy, cranial nerve dysfunction including deafness, optic atrophy or Wernicke-like syndrome), ataxia, or extrapyramidal (dystonia) symptoms, global cognitive dysfunction (dementia or mental retardation (30%)), spastic paresis, myoclonic jerks and seizures, peripheral demyelinating polyneuropathy, motor decline and unconsciousness with lactic acidosis. In addition, insulin-resistant diabetes mellitus, muscular weakness, intractable nausea and vomiting, and anemia can occur. The disease can be intermittent progressive or remitting/relapsing. CSF protein may be increased. Brain MRI shows abnormal high intensities in basal ganglia, particularly putamen, on T2 weighted images, bilateral medial regions of the thalamus, brainstem and periaqueductal gray matters. Proton MRS may show elevated lactate level in involved regions of the brain. Ragged red fibers can be found on muscle biopsy with increased succinic dehydrogenase activity and cytochrome oxidase negative fibers in almost 90% of cases. Pre- and postprandial serum and CSF lactate and pyruvate are useful in the diagnosis. Serum lactate is increased in 50% of patients but is less sensitive than CSF lactate. Pyruvate dehydrogenase deficiency (or Lactic and Pyruvate Acidemia with Episodic Ataxia and Weakness) presents with episodic ataxia, seizures, and hypoglycemic episodes and may mimic SNE. Serum and urine amino acid analyses reveal hyperalaninemia. Treatment for SNE is empirical but the administration of thiamine, coenzyme Q10 have been used. The prognosis is usually bad with survival rates less than a few years after onset.

Primary CNS infections: These include cerebritis/abscess, cerebellitis, herpes encephalitis (multiple small infarcts, can be caused by HZV hence PCR test of CSF crucial), Japanese encephalitis, Lyme disease, TB, brucellosis (exposure to raw milk) and fungal infections (both involve basal meninges and cause cranial nerve abnormalities and low glucose in CSF, risk factors for fungal infections), CJD and nvCJD, Whipple disease, toxoplasmosis, enteroviruses, HSV, HIV, hepatitis C, HTLV-1 either primary or opportunistic infection (acute, rapidly fatal meningoencephalitis or chronic encephalopathy), cysticercosis, SSPE, neurosyphilis, multifocal cerebral lesions or brain abscesses (aspergillosis, Actinomycetes, Nocardia, and pseudallescheria). These are likely to introduce CSF changes. Fungal infections prevail in immunocompromised patients, organ transplantation, diabetes, or travel to remote tropical locations.

West Nile fever: Virtually all continents have been infested with this arthropod-borne  (Flavivirus) febrile illness. Birds are the natural hosts for the virus and the vector is a mosquito.  The incubation period varies between 2 - 15 days. Usually the symptoms are mild (flu-like syndrome including fever (90%), muscle weakness (54%), headache often retro-orbital pain (46%), conjunctivitis, lymphadenopathy, arthralgia (17%), myalgia (14%), and rash (22%)), though can also cause the following neurologic syndromes: meningoencephalitis with or without muscle weakness, myelitis (polio-like syndrome consisting of asymmetric flaccid paralysis with fasciculations and areflexia), aseptic meningitis (30%), mild headache syndrome with fever, GBS (5-10%) and mostly axonal polyneuropathy. Besides these neurological features myocarditis, hepatitis and pancreatitis can occur. Age seems the most significant risk factor for severe neurologic disease. The diagnosis is based on serum and CSF IgM capture ELISA test for West Nile virus, and PCR in the CSF. Since IgM antibodies do not cross the BBB, their detection in the CSF strongly suggests CNS infection. CSF findings are otherwise non-specific (aseptic meningitis - lymphocytic pleocytosis (unless it is performed very early in the illness, in which case the CSF leukocyte count may not be elevated) with elevated protein and normal glucose). Over 50% of patients have peripheral leucocytosis and 25% leucopenia. Neuroimaging is usually normal, however in about 1/3 of patients the MRI demonstrates enhancement of the leptomeninges, periventricular areas, thalamus and/or basal ganglia. Risk factors for the infection includes occupational exposure to mosquitoes (airconditioning systems, outdoor work, etc.). Treatment is supportive. Mortality ranges from 3 to 15%.

Anthrax meningoencephalitis: Nicknamed ‘meningoencephalitis with hemorrhagic CSF’. The prodromal period is about 1 - 6 days and consist of fever, headache, nausea and vomiting in association with alteration in the level of consciousness, focal or generalized seizures, focal neurological deficits, cranial neuropathies. Nuchal rigidity may be prominent as anthrax causes leptomeningeal and SAH. With inhalation anthrax there may be additional features prior or during the meningoencephalitis: malaise, myalgias, nonproductive cough, chest pain, dyspnea and stridor. CSF may be cloudy or hemorrhagic. The opening pressure is elevated, there is polymorphonuclear pleocytosis, increased protein content and decreased glucose levels. Gram stain of the CSF reveals large gram-positive bacilli. Hemorrhagic CSF should not be mistaken for bloody tap (differential cell count between 1^st and 4^th tube). A > 4-fold increase in levels of serum IgG (ELISA) can be demonstrated between the acute and convalescent sera (this will however take 28 days to occur). Brain MRI may show focal intracerebral hemorrhage, SAH, diffuse cerebral edema or prominent leptomeningeal enhancement. Anthrax meningoencephalitis is fatal in 94% of cases with 75% of patients expiring within 24 hours of presentation.

Eastern equine encephalitis (EEE): This encephalopathy is the most severe of the mosquito-borne encephalitides, associated with 30% mortality. Serum and CSF anti-EEE IgM and IgG antibodies are diagnostic.

Herpes simplex encephalitis (HSE): This form of encephalitis accounts for about 10% of all cases of encephalitis and is almost invariably caused by HSV-1. The illness presents as a subacute encephalopathy in the absence of focal neurologic findings or evidence of systemic illness. It rarely coincides with herpetic lesions of the oral mucosa. Many patients present with an initial prodromal phase of "creeping" progression (fever (90%) and headache (80%) of relatively rapid onset), during which the disease may appear to smolder for a time before entering into a phase of rapid decline (alterations in consciousness confusion, lethargy (97%), behavioral symptoms (personality changes and psychosis) (70%) or focal and generalized seizures, aphasia, or hemiparesis). Uncal herniation due to edema may occasionally occur during the first days of the illness. However coma may also result from spread to the mesencephalon. CSF analysis reveals often increased pressure, invariably lymphocytic pleocytosis (10-500/mm³) with increased protein (100 mg/dl), normal or moderately decreased glucose and, rarely, red cells (bloody tap). The latter is not diagnostic but suggestive. Occasionally, polymorphonuclear pleocytosis may be found. 4% of patients with confirmed HSE have an initially normal cell count on the first LP, while 13% may have an initially normal CSF protein. EEG in HSV-1 may show PLEDS (2- to 3- Hz) in the inferior frontal and temporal lobes (84% sensitivity but only 32% specificity). MRI findings in HSV-1 encephalitis are abnormally high signal on T2 weighted images and swelling within the medial and inferior temporal/frontal lobe. PCR CSF study is diagnostic (sensitivity 95% and specificity 100%) and currently replaces the need for brain biopsy. However PCR for HSV may become positive as late as 7 days and remains positive the first 10 days. Thereafter the likelihood of finding a positive PCR drops to <30%. HSV-1 PCR should be repeated if first test is negative. The PCR remains positive for 2-5 days after initiation of acyclovir. HSV antibodies appear in the CSF after 8-12 days and increase the first 2 to 4 weeks. A serum/CSF ratio of <20 is considered positive. Brain biopsy should be reserved for those patients not responding to acyclovir or who have an unknown abnormality on neuroimaging. Diffusion-weighted brain MRI may be used to follow treatment efficacy and determine treatment end-point (in contrast with T2 weighted images, increased signal intensities disappear on diffusion-weighted MRI). Citrullinemia may mimic HSE on MRI. Given the documented efficacy and relatively modest toxicity of acyclovir (10-15 mg/kg tid i.v. for 14 days), empiric treatment with antiviral therapy should be initiated on suspicion of HSE, instead of waiting for confirmation of the diagnosis. In case of viral resistance to acyclovir (mass effect from edema or hemorrhage, seizure activity precipitated by persisting irritation), or of unfavorable drug pharmacokinetics, as causes of poor clinical response to therapy, foscarnet should be added to the patient's regimen. Anticonvulsives should be initiated only when seizures occur. Untreated the mortality rate reaches 70%. Over 40% of patients have no sequellae after 2 years, whereas 53% expired or are severely handicapped. Initiation of the therapy within 4 days generally results in a survival rate of over 90%. Empiric antiviral therapy should be continued in patients with clinically suspected HSE even if the initial PCR studies of CSF are negative, particularly in those patients studied early in the course of illness. Differential diagnosis include St. Louis encephalitis (mosquito-borne, humid weather, Southern states of the US), AHLE, subdural empyema and cerebral abscess (bacterial, listerial, rickettsial, fungal and mycoplasmal), TB meningitis, HIV and opportunistic infections (cryptococcal, mucormycosis infections, toxoplasmosis), SLE, bacterial endocarditis, malaria, septic CVT, tumor, ADL and stroke (particularly when presenting with aphasia).

Central European Encephalitis (CEE): Louping ill virus, Far Eastern tick born encephalitis (FEE) and CEE are distinct viruses. CEE is an arbovirus and is contracted by tick bite in endemic areas in southern Germany or Austria. Incubation period is 1 to 3 weeks giving way to an influenza-like syndrome, then followed by: either meningoencephalitis syndrome or pseudo-poliomyelitis syndrome with rapid-onset or progressive weakness of pontomesencephalic or caudal cranial nerves with early progressive respiratory failure, proximal, and arm muscles more than distal and leg muscles (cervicothoracic radiculomyelitis) without sensory deficit. No or few signs of meningoencephalitis. Serology of CEE is positive in serum and CSF. CSF shows lymphomononuclear (20 – 60%) and polymorphonuclear (40 – 80%) pleocytosis with cell counts ranging from 63 to 2,133/mL and CSF protein from 110 to 240 g/L at initial presentation. Electrophysiological studies show LMN damage. Most patients recover completely. Fatality rates range from 0.5-5%. Prognostic factors for unfavorable outcome: rapid progression and severe paralysis at disease onset, age, respiratory failure, and concomitant involvement of cranial nerves. Differential diagnosis include: enterovirus, neuroborreliosis, axonal form of GBS, acute motor neuropathies, MG and epidural and spinal abscesses.

Nipah encephalitis: Infected pigs are the human reservoir for this disease. In addition to significant hypertension and tachycardia, fever, headache, altered mental status, areflexia, cerebellar and brainstem signs, and segmental myoclonus are common clinical findings. Brain MRI reveals multiple, small white matter lesions. Outbreaks of this potential fatal type of encephalitis occurred in Malaysia.

Varicella zoster encephalitis: Besides cerebellar ataxia which is usually self-limiting and resolves within a few weeks, meningoencephalitis is another but more severe complication of varicella. Advanced age, immunosuppression and disseminated cutaneous zoster are predisposing factors. Headache, fever and vomiting are often accompanied by an altered sensorium with seizures occurring in over one third of cases. Focal neurology symptoms (stroke) may occur due to large vessel vasculitis or granulomatous arteritis. Myelitis may also occur. Contralateral hemiplegia in patients with ophthalmic zoster accounts for up to one third of cases of CNS abnormalities with herpes zoster. CSF analysis shows changes typical for aseptic meningitis with oligoclonal bands and intrathecal immunoglobulin synthesis. The EEG is usually diffusely abnormal. CSF culture and CSF VZV antibodies may be detected. PCR is diagnostic in associated HZV meningitis.

Salmonella encephalopathy: Typhoid fever can present with an encephalopathy consisting of seizures, rigidity and confusion. Neuroimaging may show cerebral edema, ADEM or cerebellar atrophy. Cerebellar ataxia may occur.

Cerebral malaria: This is a diffuse encephalopathy caused by P. falciparum asexual parasitemia. Fever, unconsciousness with divergent gaze and a certain degree of meningismus may be present. Multisystem dysfunction is usually found with anemia, jaundice and acidosis (Kussmaul breathing). Hypoglycemia occurs in almost 10% of patients suffering from severe cerebral malaria. Additonal findings include retinal hemorrhages, bruxism and seizures (50%) Other encephalopathies, especially bacterial meningitis and viral encephalitides need to be excluded. The overall mortality is about 20%.

Brain hemorrhages and infarcts: These can be the result of infections with opportunistic infections (mucor and aspergillus), Binswanger disease, TTP, DIC, hypercoagulability (e.g. antiphospholipid syndrome, mucinous carcinoma), noninfective endocarditis or infective endocarditis (Staphylococcus aureus). CAA and granulomatous angiitis presents with acute (days to weeks) headache, fever, disorientation, confusion, inflammatory syndrome (leucocytosis with left shift and normal or increased ESR). Brain MRI shows small-vessel disease. Massive infarctions in the middle cerebral artery give rise to  hemiplegia with stupor. Brainstem and cerebellar hemorrhages or infarctions may result in severe intracranial hypertension with coning.

Tumors: Meningeal carcinomatosis (particularly related to hematological disorders), metastatic carcinoma, leukemia or lymphoma. Intravascular lymphoma (neoplastic angioendotheliosis or neurolymphomatosis) results in skin and CNS abnormalities. Typical key features are headache, multifocal neurologic signs and a progressive course. MRI shows small foci of hyperintensity or large areas of signal change in white matter of the cortex. Angiographic findings are usually normal (blood vessels involved are too small). Difficult to distinguish from PACNS. Lymphomatoid granulomatosis shows slightly elevated CSF protein (<100), WBC normal, lungs invariably involved, skin and kidneys affected in 50% of patients. IgG CSF may be elevated if tumor cells are of B-cell origin. Skin, meningeal or brain biopsy can be diagnostic. Sensorimotor neuropathy is typical. Another entity is carcinomatous encephalitis (miliary metastasis) which can be diagnosed on the basis of clinical picture of encephalopathy and MRI appearance (multiple high signal foci in the brain parenchyma supra and infratentorial on T2, in the absence of edema or mass effect) in a patient with a proven tumor.

Paraneoplastic encephalomyeloneuritis: Small cell lung, testicular or prostate cancer is most commonly associated with this paraneoplastic syndrome. A variety of clinical findings may be present: cerebellar degeneration, limbic encephalitis, bulbar encephalitis, ALS-like syndrome, dorsal sensory neuronopathy, autonomic neuropathy. Progression may be rapid or progressive. CSF may be inflammatory with lymphocytic pleocytosis and increased proteins. IgG levels are usually increased with oligoclonal bands. Anti-Hu antibodies are typically found in serum and CSF. Less commonly anti-Ta, anti-amphiphysin or anti-CV2 antibodies may be found. Limbic encephalitis can also be a presentation of autoimmune encephalitis.

Reversible posterior leucoencephalopathy (RPLE): This hypertensive-induced encephalopathy consists of a pentade of headache (73%), nausea or vomiting (43%), abnormal gait (26%), altered alertness (ranging from drowsiness and diminished spontaneity to frank stupor) (23%) and behavior, seizures (17%), and abnormalities of visual perception (ranging from blurred vision to frank cortical blindness) (34%) associated with, transient, predominantly parieto-occipital lesions on MRI. CT scan and MRI frequently show edema in the occipital regions "posterior reversible leucoencephalopathy". Since brain CT scan is often negative MRI has become the procedure of choice when this syndrome is suspected. Predominant involvement of white matter and involvement of the gray-white matter junction, with edema extending into the cortex, may be common. Diffusion-weighted MRI is able to differentiate between true stroke and RPLE, in that diffusion images are normal in RPLE. Common precipitants include acute elevations of blood pressure (hypertensive encephalopathy)(e.g. following associated with post-streptococcal glomerulonephritis), acute renal decompensation, the peripartum period (eclampsia), and treatment with immunosuppressive drugs such as cyclosporine, FK-506 (tacrolimus), α-interferon, chemotherapy for ALL or mycophenolate derivatives.

Inflammatory disorders: Neurosarcoidosis (meningeal involvement, often basilar), lymphomatoid granulomatosis, PACNS (ESR raised in 2/3 and leucocytosis in WBC in 50% of patients). Biopsy diagnostic but can be negative. Other inflammatory diseases include: Churg-Strauss syndrome (asthma, eosinophilia), Wegener granulomatosis, SLE, Behçet disease and PAN. Susac syndrome: This syndrome usually occurs in young women (female-to-male ratio is 3:1) in the 2^nd to 6^th decades of life (usually 20-40 years of age). The complete syndrome consists of a triad of encephalopathy, usually bilateral branch retinal artery occlusions (often only diagnosed by ophthalmologist), and hearing loss. However the three elements may not all be present at the onset. The encephalopathy manifests with headache, confusion, memory loss, behavioral changes, dysarthria, and occasional mutism. The retinal occlusion may be extensive or subtle; if the posterior pole of the retina is involved, patients may complain of impaired vision. Retinal artery occlusion may be the presenting features of the disease, or occur later in the clinical course. The hearing loss is usually bilateral and frequently associated with tinnitus and vertigo; it may be the presenting feature or develop later. The clinical course is self-limiting usually ranging 2 to 4 years, after which patients will then stabilize with varying degrees of cognitive disturbance, impaired hearing, and vision loss. An immune response etiology is presumed. MRI is invariably abnormal, particularly in encephalopathic onset patients, but the white matter lesions are often attributed to demyelination (MS or ADEM). All patients present with cerebral white matter lesions involvement of the corpus callosum (e.g. T1-weighted image may show central callosal holes; sagittal proton density weighted image may show callosal “snowballs”, double-dose gadolinium T1-weighted image with magnetization transfer may show numerous enhancing lesions of white, deep, and gray matter, and leptomeninges). Deep gray lesions are found in 70% and leptomeningeal enhancement in 33% of cases. A normal MRI might be predicted in patients with only hearing loss and retinal artery occlusion, but without encephalopathy.