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472 Laboratory Medicine in Psychiatry and Behavioral Science
Manic episode (continued)
Laboratory testing
(continued)
In the presence of risk factors or suggestive history, the following tests
should also be considered:
• Urine toxicology
• HIV testing
• Blood alcohol level
• ESR or CRP
• Vitamin B
12
or folate levels
• Urine pregnancy testing
• EEG (to exclude epileptiform activity)
• Brain MRI or head CT
If any of the medical conditions listed in the Clinical Findings section
above as a cause of mania is suspected, further laboratory workup
should be performed as detailed in the entries for those conditions.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition,
Text Revision. Washington, DC, American Psychiatric Association, 2022
Bhatt K, Yoo J, Bridges A: Ketamine-induced manic episode.Prim Care Companion CNS Disord
23(3):20l02811, 2021
Jiménez-Fernández S, Solis MO, Martínez-Reyes I, et al: Secondary mania in an elderly patient during SARS-
CoV-2 infection with complete remission: a 1-year follow-up.Psychiatr Danub 33(3):418–420, 2021
Miola A, Dal Porto V, Meda N, et al: Secondary mania induced by TNF-alpha inhibitors: a systematic re-
view.Psychiatry Clin Neurosci 76(1):15–21, 2022
Park JH, Kummerlowe M, Gardea Resendez M, et al: First manic episode following COVID-19 infec-
tion.Bipolar Disord 23(8):847–849, 2021
Ramírez-Bermúdez J, Marrufo-Melendez O, Berlanga-Flores C, et al: White matter abnormalities in late on-
set first episode mania: a diffusion tensor imaging study.Am J Geriatr Psychiatry 29(12):1225–1236, 2021
Rao S, Sunkara A, Ashwath A, et al: Lupus cerebritis refractory to guideline-directed therapy: a case re-
port. J Investig Med High Impact Case Rep 9:23247096211008708, 2021
Sami M, Khan H, Nilforooshan R: Late onset mania as an organic syndrome: a review of case reports in
the literature.J Affect Disord 188:226–231, 2015
Sloan S, Dosumu-Johnson RT: A New onset of mania in a 49-year-old man: an interesting case of Wilson
disease.J Psychiatr Pract 26(6):510–517, 2020
Tohen M, Shulman KI, Satlin A: First-episode mania in late life.Am J Psychiatry 151(1):130–132, 1994
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473 Diseases and Conditions
Marchiafava-Bignami disease (MBD)
Clinical findings MBD is an uncommon disorder characterized by demyelination and
necrosis of the corpus callosum that has been identified mainly among
males with chronic alcoholism and malnutrition. Callosal involvement
can be partial or complete and may or may not be reversible with treat-
ment. Cortical structures may also be involved (Morel’s laminar sclero-
sis). The pathophysiology of MBD is thought to involve alcohol toxicity,
B vitamin deficiencies (particularly thiamine), and possibly other fac
-
tors. MRI findings suggest that cytotoxic edema is present early in the
disease course, with demyelination and necrosis following.
Prominent signs and symptoms of MBD include the following:
• Delirium, stupor, coma
• Disorientation, amnesia
• Mutism
• Callosal disconnection syndrome
• Behavioral abnormalities (apathy, depression, psychosis)
• Seizures
• Gait disturbance
• Pyramidal tract signs
• Rigidity
• Dysarthria
• Primitive reflexes
• Visual disturbances (diplopia or gaze palsy)
Disruption of commissural fibers results in a characteristic callosal dis-
connection syndrome. Because language is processed mostly in the left
hemisphere, the right hemisphere becomes isolated from language in-
formation, causing left hand anomia, left hand agraphia, and left ear
extinction. In addition, knowledge required to perform learned/skilled
motor acts is also processed mostly in the left hemisphere, so the right
hemisphere becomes isolated from praxis information, causing left
hand apraxia and difficulty in performing purposeful actions with the
left hand. Other disconnection syndromes include alien hand, way-
ward hand, and intermanual conflict.
Laboratory testing Because several other conditions affecting the same patient popula-
tion—delirium tremens, Wernicke’s encephalopathy, and osmotic
demyelination—may present with similar symptoms, laboratory eval-
uation using MRI has proven a critical component of early diagnosis in
MBD. Diffusion-weighted MRI shows the earliest evidence of lesions
compatible with MBD, at the stage at which treatment may forestall
progression to coma and death. This window is within 2 weeks of the
onset of symptoms.
• The study of choice for diagnosing MBD is diffusion-weighted
MRI, which shows hyperintensities in affected areas.
• Recovery may best be monitored using diffusion tensor imaging
and fiber tracking.
• Early phase edema of the corpus callosum and other involved ar-
eas may appear as hypointense areas on T1-weighted images and
hyperintense areas on T2-weighted FLAIR images.
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474 Laboratory Medicine in Psychiatry and Behavioral Science
Marchiafava-Bignami disease (MBD) (continued)
Laboratory testing
(continued)
• The “sandwich sign” on sagittal T1-weighted and FLAIR images
indicates involvement of the central portion of the corpus callosum
with sparing of the dorsal and ventral layers.
• Lesions characteristic of MBD seen on admission are frequently
persistent.
DeDios-Stern S, Gotra MY, Soble JR: Comprehensive neuropsychological findings in a case of Marchi-
afava-Bignami disease. Clin Neuropsychol 35(6):1191–1202, 2021
Dong X, Bai C, Nao J: Clinical and radiological features of Marchiafava-Bignami disease.Medicine (Bal-
timore) 97(5):e9626, 2018
Hillbom M, Saloheimo P, Fujioka S, et al: Diagnosis and management of Marchiafava-Bignami disease: a
review of CT/MRI confirmed cases.J Neurol Neurosurg Psychiatry 85(2):168–173, 2014
Kakkar C, Prakashini K, Polnaya A: Acute Marchiafava-Bignami disease: clinical and serial MRI correla-
tion.BMJ Case Rep 2014:bcr2013203442, 2014
Kinsley S, Giovane RA, Daly S, Shulman D: Rare case of Marchiafava-Bignami disease due to thiamine
deficiency and malnutrition.BMJ Case Rep 13(12):e238187, 2020
Li W, Ran C, Ma J: Diverse MRI findings and clinical outcomes of acute Marchiafava-Bignami dis-
ease. Acta Radiol 62(7):904–908, 2021
Namekawa M, Nakamura Y, Nakano I: Cortical invo lvement in Marchiafava-Bignami disease can be a pre-
dictor of a poor prognosis: a case report and review of the literature.Intern Med 52(7):811–813, 2013
Tung CS, Wu SL, Tsou JC, et al: Marchiafava-Bignami disease with widespread lesions and complete re-
covery. AJNR Am J Neuroradiol 31:1506–1507, 2010
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475 Diseases and Conditions
Meningitis
Clinical findings Meningitis refers to an inflammation of the layers of tissue surround-
ing the brain and spinal cord and the enclosed subarachnoid space that
is caused by infectious or non-infectious pathologies. Meningeal infec
-
tions include bacterial, viral, mycobacterial, spirochetal, parasitic, and
fungal diseases that reach the CNS by crossing the blood-brain barrier
directly or by infecting immune cells that then cross the blood-brain
barrier. Aseptic meningitis refers to inflammation caused by patho
-
gens other than pus-producing bacteria (most commonly viruses) or
by non-infectious conditions. Except for viral meningitis, mortality
rates in infectious meningitis remain high, particularly for tuberculous
and cryptococcal pathogens in immunocompromised individuals.
Prompt diagnosis and treatment of all cases is essential.
Non-infectious causes of meningitis include neoplastic, autoimmune,
and chemical pathologies. Neoplastic meningitis can be a complication
of either hematological malignancies or solid tumors (most commonly
breast cancer, non-small-cell lung cancer, or malignant melanoma).
Autoimmune meningitis can be associated with diseases such as rheu-
matoid arthritis and SLE. Chemical- or drug-induced meningitis can
result from direct meningeal irritation (with intrathecally adminis
-
tered drugs) or hypersensitivity reactions.
Signs and symptoms of meningitis depend on the cause and chronicity
of symptoms.
Bacterial meningitis is characterized by the following:
• Fulminant to subacute onset
• Classic triad for meningitis: fever, headache, and neck rigidity
(may be severe)
• Delirium, lethargy, coma
• Nausea and vomiting
• Photophobia
• Seizures (partial or generalized)
• Evidence of increased intracranial pressure: stupor, papilledema,
dilated and poorly reactive pupils, sixth nerve palsy, decerebrate
posturing, bradycardia, hypertension, and irregular respiration
• Skin rash with meningococcemia
Viral meningitis is characterized by the following:
• Classic triad for meningitis: fever, headache, and neck rigidity
(mild)
• Constitutional symptoms: malaise, myalgia, anorexia, nausea,
vomiting, diarrhea, abdominal pain
• Lethargy or drowsiness (stupor or delirium suggests another diag-
nosis)
Chronic meningitis is diagnosed when signs and symptoms are pres-
ent for ≥4 weeks. In chronic disease, signs and symptoms include the
following:
• Fever
• Headache
• Lethargy
• Mental status changes
• Hearing loss
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476 Laboratory Medicine in Psychiatry and Behavioral Science
Meningitis (continued)
Clinical findings • Diplopia
(continued)
• Cognitive impairment
• Hydrocephalus, elevated intracranial pressure (especially with
cryptococcus)
• Seizures
• Stroke-like episodes
• Radiculopathies (spinal cord involvement)
• Less common: signs of meningeal irritation or neck rigidity
Laboratory testing CSF testing
The mainstay of testing for infectious meningitis involves lumbar
puncture (LP) with CSF sampling. Before an LP, a CT scan should be
performed in certain patients to identify those at risk of brain hernia-
tion, including the immunocompromised, those with a history of CNS
disease (e.g., mass, stroke, or focal infection), those with a seizure
within the past week, or those with papilledema, abnormal level of
consciousness, or focal neurological deficit (e.g., dilated nonreactive
pupil, gaze palsy, or arm/leg drift).
When an LP is performed, the opening pressure is measured and fluid
sent for the following:
• Chemistries (total protein and glucose)
• Cell count (and differential)
• Microbiology (Gram stain and culture)
About 6 mL of fluid is sufficient for routine testing, but if tuberculosis
or fungal meningitis is suspected, a large-volume sample of 10–20 mL
should be sent to the laboratory. Some CSF should be saved for further
studies.
In general, meningitis caused by bact eria or mycobacteria is associated
with higher total protein, lower CSF glucose, and greater elevation in
WBC count than that caused by viral disease.
The diagnosis of bacterial meningitis is made by Gram stain and cul-
ture of CSF. PCR testing panels for multiple pathogens should be per-
formed where available. Technologies such as matrix-assisted laser
desorption/ionization–time of flight (MALDI-TOF) mass spectrome
-
try testing for multiple pathogens should be considered.
For tuberculous meningitis, acid-fast bacillus smear and culture may
still be used but are insensitive, and culture takes weeks to return. Au-
tomated PCR could also be used, but the commercially available test
Xpert MTB/RIF Ultra (Mycobacterium tuberculosisand rifampicin) is
now a first-line recommendation for detection of tuberculosis, with in
-
formation on drug sensitivity and drug resistance included. The result
is returned within hours.
The diagnosis of cryptococcal meningitis is based on the detection of
cryptococcal antigen in CSF via lateral flow immunoassay. Culture
may also be helpful.
For viral meningitis, the focus of testing is PCR amplification of viral
DNA.
For chronic meningitis, serial LP (up to 3 times) may be indicated for
fungal and mycobacterial cultures if the initial results are negative. Re-
peat testing of CSF cytology may also be indicated if initially negative.
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477 Diseases and Conditions
Meningitis (continued)
Laboratory testing
(continued)
Metagenomic next-generation sequencing (NGS) allows screening for
a range of bacterial, fungal, parasitic, and viral pathogens in a single
assay. Because this area of research is rapidly evolving, inquiry should
be made to the laboratory to determine what is available for CSF test-
ing. At this writing, NGS is used in tandem with traditional microbio-
logical testing.
Neuroimaging
In general, neuroimaging does not facilitate the diagnosis of meningi-
tis but may be useful in identifying parameningeal causes of CSF ab-
normalities or complications of meningitis such as hydrocephalus,
brain abscess, or subdural empyema. In addition, neuroimaging
should be performed in patients with seizures, focal neurological
signs, altered consciousness, or an atypical CSF profile. In bacterial
meningitis, MRI is preferred to CT because of its ability to detect
edema and ischemia.
Abussuud ZA, Geneta VP: Rheumatoid meningitis. World Neurosurg 137:98–101, 2020
Aksamit AJ: Chronic meningitis. N Engl J Med 385(10):930–936, 2021
de Oliveira L, Melhem MSC, Buccheri R, et al: Early clinical and microbiological predictors of outcome in
hospitalized patients with cryptococcal meningitis. BMC Infect Dis 22(1):138, 2022
Guziejko K, Czupryna P, Zielenkiewicz-Madejska EK, Moniuszko-Malinowska A: Pneumococcal menin-
gitis and COVID-19: dangerous coexistence: a case report. BMC Infect Dis 22(1):182, 2022
Heller HM, Gonzalez RG, Edlow BL, et al: Case 40–2020: a 24-year-old man with headache and COVID-
19. N Engl J Med 383(26):2572–2580, 2020
Kohil A, Jemmieh S, Smatti MK, Yassine HM: Viral meningitis: an overview.Arch Virol 166(2):335–345, 2021
Méchaï F, Bouchaud O: Tuberculous meningitis: ch allenges in diagnosis and management.Rev Neurol
(Paris) 175(7–8):451–457, 2019
Poplin V, Boulware DR, Bahr NC: Methods for rapid diagnosis of meningitis etiology in adults.Biomark
Med 14(6):459–479, 2020
Rigakos G, Liakou CI, Felipe N, et al: Clinical presentation, diagnosis, and radiological findings of neo-
plastic meningitis. Cancer Control 24(1):9–21, 2017
Straus SE, Thorpe KE, Holroyd-Leduc J: How do I perform a lumbar puncture and analyze the results to
diagnose bacterial meningitis? JAMA 296:2012–2022, 2006
Vasudeva SS: Meningitis workup, in Medscape: Drugs and Diseases: Infectious Diseases, 2022. Available
at:
https://emedicine.medscape.com/article/232915-workup. Accessed March 2022.
Wilson MR, Sample HA, Zorn KC, et al: Clinical metagenomic sequencing for diagnosis of meningitis and
encephalitis. N Engl J Med 380(24):2327–2340, 2019
Xing XW, Zhang JT, Ma YB, et al: Metagenomic next-generation sequencing for diagnosis of infectious
encephalitis and meningitis: a large, prospective case series of 213 patients.Front Cell Infect Microbiol
10:88, 2020
Yelehe-Okouma M, Czmil-Garon J, Pape E, et al: Drug-induced aseptic meningitis: a mini-review.Fun-
dam Clin Pharmacol 32(3):252–260, 2018
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478 Laboratory Medicine in Psychiatry and Behavioral Science
Mercury poisoning
Clinical findings The chemical element mercury is known to be toxic to humans and
other animals, and although mercury exposure occurs from a variety of
everyday activities, the long-term and cumulative effects of exposure
have been inadequately characterized. Mercury occurs in three forms:
elemental, organic, and inorganic.
• Elemental mercury exposure occurs primarily from dental amalgam
and in occupations such as dentistry, electroplating, metallurgy,
mining, and a long list of others in which mercury is used in pro
-
cessing. Toxicity arises from breathing mercury vapor, which can
easily be generated from something as simple as drilling a “silver”
filling or when mercury is removed from an enclosed container
such as a thermometer. The vapor is lipid-soluble and readily
crosses the blood-brain barrier.
• Inorganic mercury has been used in cosmetics and medicines and as
a topical antiseptic. Industrial exposure occurs in the tanning ind
-
ustry, in taxidermy, in the manufacturing of fireworks, and in dye
production. This form can be found in patent medicines, Asian
herbal preparations, and certain skin creams manufactured
outside the United States. Toxicity arises from inhalation, inges
-
tion, or absorption through the skin.
• Organic mercury exposure occurs primarily through fish consump-
tion because other uses of this form have been banned or severely
curtailed. This form is highly toxic and a known teratogen. Accord-
ingly, recommendations to limit fish intake (to three or fewer serv-
ings per week) and to stay informed as to current data regarding
fish species have been published. One excellent source of informa-
tion is the Environmental Working Group’s Consumer Guide to Sea-
food cited in the reference list below.
Exposure to mercury likely poses a greater risk among specific sub-
populations, including pregnant females and their developing fetuses,
nursing females and their infants, children, people with preexisting
neurological or renal disease, those with known sensitivity to metals,
and possibly those with certain susceptibility genes, not all of which
are known. This latter possibility has generated concern that dental
amalgam may not be safe for some individuals.
Neuropsychiatric signs and symptoms of mercury poisoning include
fatigue, headache, apathy, irritabilit y, emotional instability, psychosis,
amnestic mild cognitive impairment, paresthesias, parkinsonism,
ataxia, postural and action tremor, myoclonus, neuromyotonia,
choreoathetosis, deafness, dysarthria, dysphagia, visual field constric-
tion, and coma. Some cases have a fatal outcome.
With inhalation of elemental mercury, pulmonary symptoms are seen,
including burning in the mouth and lungs, cough, difficulty breathing,
and chest tightness. With ingestion of mercury salts or organic mer
-
cury, GI symptoms are seen, including nausea, vomiting, and diarrhea.
Decreased urine output and renal toxicity may also be seen. High mer-
cury load is a risk factor for ischemic heart disease and may be a risk
factor for neurodegenerative disease.
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479 Diseases and Conditions
Mercury poisoning (continued)
Laboratory testing Reference values
• Whole blood mercury, inorganic: ≤ 10.0 μg/L
Urine:
• Urine mercury/24 hours: 0.0–20.0 μg/day
• Urine mercury/volume: 0.0–5.0 μg/L
• Mercury-to-creatinine ratio: 0.0–20 μg/gCR
The mercury level in whole blood is used for evaluation of acute expo-
sure to inorganic forms because blood levels rise and fall quickly over
several days. Exposure to organic mercury may contribute to elevated
total mercury levels, with blood concentrations of 20–50 μg/L. Dietary
and other restrictions are required before testing; see ARUP Laborato
-
ries reference cited below.
Urine mercury levels are used for evaluating acute or chronic elemental
or inorganic mercury exposure and for monitoring treatment. Dietary
and other restrictions are required before testing (see ARUP Laboratories
reference). Twenty-four-hour urine levels of 30–100 μg/L are associated
with tremor and subclinical neuropsychiatric symptoms, while levels
>100 μg/L are associated with overt neuropsychiatric impairment.
Testing of other samples (e.g., blood, hair, toenails) for chronic mercury
poisoning is less useful because the samples are not likely to reflect
distant neuronal injury.
ARUP Laboratories: Mercury, urine, in Laboratory Test Directory. Salt Lake City, UT, ARUP Laboratories,
2022. Available at:
https://ltd.aruplab.com/Tests/Pub/0025050. Accessed March 2022.
ARUP Laboratories: Mercury, whole blood, in Laboratory Test Directory. Salt Lake City, UT, ARUP Lab-
oratories, 2022. Available at: https://ltd.aruplab.com/Tests/Pub/0099305. Accessed March 2022.
Cariccio VL, Samà A, Bramanti P, Mazzon E: Mercury involvement in neuronal damage and in neurode-
generative diseases. Biol Trace Elem Res 187(2):341–356, 2019
Ekino S, Susa M, Ninomiya T, et al: Minamata disease revisited: an update on the acute and chronic man-
ifestations of methyl mercury poisoning. J Neurol Sci 262:131–144, 2007
Environmental Working Group: EWG’s Consumer Guide to Seafood. Washington, DC, Environmental
Working Group, 2014. Available at:
https://www.ewg.org/consumer-guides/ewgs-consumer-guide-
seafood. Accessed March 2022.
Homme KG, Kern JK, Haley BE, et al: New science challenges old notion that mercury dental amalgam
is safe.Biometals 27(1):19–24, 2014
Hu XF, Lowe M, Chan HM: Mercury exposure, cardiovascular disease, and mortality: a systematic review
and dose-response meta-analysis. Environ Res 193:110538, 2021
Jackson AC: Chronic neurological disease due to methylmercury poisoning.Can J Neurol Sci 45(6):620–
623, 2018
Johnson-Arbor K, Schultz B: Effective decontamination and remediation after elemental mercury expo-
sure: a case report in the United States. J Prev Med Public Health 54(5):376–379, 2021
Kolipinski M, Subramanian M, Kristen K, et al: Sources and toxicity of mercury in the San Francisco Bay
Area, spanning California and beyond. J Environ Public Health 2020:8184614, 2020
Ran E, Wang M, Yi Y, et al: Mercury poisoning comp licated by acquired neuromyotonia syndrome: a case
report. Medicine (Baltimore) 100(32):e26910, 2021
Rice KM, Walker EM Jr, Wu M, et al: Environmental mercury and its toxic effects.J Prev Med Public
Health 47(2):74–83, 2014
Siblerud R, Mutter J, Moore E, et al: A hypothesis and evidence that mercury may be an etiological factor
in Alzheimer’s disease.Int J Environ Res Public Health 16(24):5152, 2019
Stratakis N, Conti DV, Borras E, et al: Association of fish consumption and mercury exposure during
pregnancy with metabolic health and inflammatory biomarkers in children.JAMA Netw Open
3(3):e201007, 2020
U.S. Food and Drug Administration: Dental amalgam fillings, in Medical Devices: Products and Medical
Procedures: Dental Devices. Washington, DC, U.S. Food and Drug Administration, 2021. Available at:
https://www.fda.gov/medical-devices/dental-devices/dental-amalgam-fillings#fish. Accessed
March 2022.
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480 Laboratory Medicine in Psychiatry and Behavioral Science
Metabolic syndrome
Clinical findings The metabolic syndrome is a group of risk factors that increase the risk
of diabetes mellitus, heart disease, and stroke. These risk factors in
-
clude hypertension, hyperlipidemia, hyperglycemia, and truncal obe-
sity (excess body fat around the waist). There is substantial evidence
that patients with psychiatric disorders are at increased risk of devel
-
oping the syndrome. This elevated risk is seen with major depressive
disorder, bipolar disorder, schizophrenia, alcohol use disorder, anxiety
disorders, PTSD, and ADHD. The extent to which psychiatric illness
itself is responsible
use remains unclear.
It is well established that certain psychotropic medications contribute
significantly to the risk of the metabolic syndrome. This is particularly
true for atypical antipsychotics (especially olanzapine and clozapine)
and, to a lesser extent, mood stabilizers and antidepressants (except
bupropion). Unlike other atypical antipsychotics, aripiprazole and
ziprasidone do not increase the risk, and there is evidence that aripip-
razole may have protective effects.
Psychiatrists and other behavioral medicine specialists are on the front
lines of management for these at-risk populations, so it is critical that
clinicians become fully aware of the need to initiate preventive mea
-
sures, to closely monitor the syndrome parameters in the course of
treatment with psychotropic drugs, and to ensure adequate treatment
of metabolic abnormalities.
Laboratory testing The metabolic syndrome is defined by three or more of the following:
• Abdominal obesity: increased waist circumference; >38–41 inches
in males and >32 inches in females
• Impaired glycemic control: fasting blood sugar 100–125 mg/dL or
HbA1C 5.7%–6.4%
• Hypertension: blood pressure ≥ 130/85 or taking medication for
hypertension
• Hyperlipidemia: fasting triglycerides >150–180 mg/dL or fasting
high-density lipoprotein cholesterol <40 mg/dL for males or
<50 mg/dL for females, or taking medication for high triglycerides
or low HDL cholesterol
Dregan A, Rayner L, Davis KAS, et al: Associations between depression, arterial stiffness, and metabolic
syndrome among adults in the UK Biobank Population Study: a mediation analysis. JAMA Psychiatry
77(6):598–606, 2020
Ijaz S, Bolea B, Davies S, et al: Antipsychotic polypharmacy and metabolic syndrome in schizophrenia: a
review of systematic reviews. BMC Psychiatry 18(1):275, 2018
Jeon SW, Kim YK: Unresolved issues for utilization of atypical antipsychotics in schizophrenia: antipsy-
chotic polypharmacy and metabolic syndrome. Int J Mol Sci 18(10):2174, 2017
Mazereel V, Detraux J, Vancampfort D, et al: Impact of psychotropic medication effects on obesity and the
metabolic syndrome in people with serious mental illness.Front Endocrinol (Lausanne) 11:573479, 2020
Penninx BWJH, Lange SMM: Metabolic syndrome in psychiatric patients: overview, mechanisms, and
implications.Dialogues Clin Neurosci 20(1):63–73, 2018
Schuster MP, Borkent J, Chrispijn M, et al: Increased prevalence of metabolic syndrome in patients with
bipolar disorder compared to a selected control group: a Northern Netherlands LifeLines population
cohort study. J Affect Disord 295:1161–1168, 2021
Zhang M, Chen J, Yin Z, et al: The association between depression and metabolic syndrome and its com-
ponents: a bidirectional two-sample Mendelian randomization study.Transl Psychiatry 11(1):633, 2021
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481 Diseases and Conditions
Metachromatic leukodystrophy (MLD)
Clinical findings MLD is a rare autosomal recessive genetic disorder arising from the ac-
cumulation of toxic metabolites known as sulfatides inside cells of the
nervous system that appear as differently colored granules under the
microscope. This toxic accumulation results in demyelination and de
-
struction of white matter. The condition is the result of deficient activity
of the lysosomal enzyme
arylsulfatase A gene (ARSA) or (in a minority of cases) in the saposin B
gene (PSAP).
Most cases of MLD come to clinical attention in early life, but up to 20%
are adult-onset, presenting from adolescence to the seventh decade and
representing a less severe form. Symptoms can progress slowly with this
form, with periods of relative stability interspersed with rapid decline.
Patients have been reported to survive up to 30 years after diagnosis.
In adult-onset MLD, the initial symptoms are predominantly neuro-
psychiatric, with motor symptoms emerging only in later stages. For
this reason, the condition is likely to be mistaken for dementia or a
primary psychiatric disorder.
Signs and symptoms include the following:
• Decreased performance at work or school
• Behavioral and personality changes—impulsiveness, irritability,
disinhibition, socially inappropriate behaviors, neglect of personal
affairs
• Cognitive impairment—dementia with prominent frontal lobe fea-
tures, memory impairment
• Depression, mood swings
• Psychosis—hallucinations (especially auditory) and delusions
(may be bizarre)
• Peripheral neuropathy
• Cerebellar ataxia
• Spasticity
• Seizures
• Optic atrophy
• Gradual loss
The diagnosis is made based on clinical findings along with the lab stud-
ies noted below. One possibly helpful non-neurological sign is cholecys-
titis arising from sulfatide accumulation in the wall of the gallbladder.
Laboratory testing The following tests are used to aid in diagnosis of MLD:
• Genetic testing for mutations in ARSA and/or PSAP. This testing
can also be used to identify carriers and for prenatal diagnosis.
• Biochemical testing for arylsulfatase A enzyme activity in leuko-
cytes or cultured skin fibroblasts. In MLD, values usually range
from undetectable to <10% of normal. A pseudo-deficiency syn-
drome exists in which values range from 5% to 20% of normal, and
clinical and MRI evidence of MLD is absent. These entities can be
distinguished with further testing such as urine sulfatide levels,
which are elevated in MLD and normal in the pseudo-deficiency
syndrome.
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