Presentation and Diagnosis of Rapidly Progressing Encephalopathy

Q: A 71-year-old woman is brought to your office by her daughter, who relays her concern that over the past three months, her mother has developed worsening anxiety, periods of confusion, and a change in her usual pleasant personality. In addition, her mother has undergone a 10-pound weight loss. Her daughter also describes several episodes where her mother sits and stares, picks at things with her hands, and occasionally smacks her lips.

The patient has been on paroxetine 20 mg daily for a depressive episode that started two years ago, following the death of her husband of 51 years. Her past health has otherwise been excellent; although she smoked for almost 40 years, she stopped smoking five years ago. On physical examination, she is afebrile. Blood pressure is measured at 110/70 mm Hg. She is withdrawn, and intermittently stares ahead without acknowledging your presence.

A firm, palpable 2-cm by 3-cm mass is noted in the left breast. On cognitive testing, she is confused regarding place, and recalls only one of the three words after a five-minute delay. Clock drawing is done without difficulty. She is able to name 12 animals in 60 seconds. There is no evidence for executive dysfunction.

What is the differential diagnosis, and what testing should be done as the next step?

A: This patient exhibits a fairly rapid onset of changes in personality, confusion, and anxiety associated with 10-pound weight loss. The history suggests an encephalopathy. Her cognitive testing reveals a short-term memory deficit. The differential is generous but includes the following:

• Brain metastasis
• Serotonin excess syndrome
• Creutzfeldt-Jakob disease
• Encephalitis

The rapidity with which the patient displayed these changes suggests a rapidly progressive encephalopathy. The etiology here could be inflammatory, infectious, neoplastic, metabolic, or vascular.

The next step would be to perform a magnetic resonance imaging (MRI) of the brain, which in this case showed increased T2 signal in the medial-temporal lobe without enhancement. An electroencephalogram (EEG) is an important test to carry out because the patient manifests evidence for complex partial seizures. Indeed, this showed focal changes within the right temporal area.

A chest x-ray is certainly indicated because of her longstanding history of smoking and her 10-pound weight loss. Herpes encephalitis is in the differential, but is not very likely, although she had no fever and the course of her symptoms has been insidious over a period of three months.

Serotonin excess syndrome would be unlikely with this dosage of paroxetine, and is usually associated with flushing, extrapyramidal signs, hypertension, and myoclonus. Creutzfeldt-Jakob disease is much more rapidly progressive with a significantly worse dementia than is seen in this case. The EEG in that situation usually shows generalized sharp waves, whereas the EEG abnormalities in the encephalopathies are usually focal, as is the case here. A metastatic lesion to the brain should enhance with contrast on MRI. Central nervous system vasculitis usually shows multiple areas of infarct on MRI.

Patients with paraneoplastic limbic encephalitis can present in several different ways: with anxiety, depression, confusion, short-term memory loss, or very rapid and unusual neuropsychiatric changes, including delirium and hallucinations, with the onset of complex partial seizures. Paraneoplastic limbic encephalitis has been most frequently associated with small-cell lung cancer, but has been described with Hodgkin’s lymphoma, testicular cancer, and breast cancer. Most patients present with personality changes, changes in affect, and alteration in cognition, along with new-onset seizure activity.

Several antibodies are associated with this disorder: antineuronal nuclear antibody type 1 (ANNA-1 or Anti-Hu), anti-Ma2, anti-CRMP5, and rarely, voltage-gated potassium-channel antibodies.

TREATMENT STRATEGY

Determining the etiology (tumor) and initiating treatment is the most important strategy associated with improvement in symptoms of the encephalitis. Some patients will benefit from immunosuppression, as there is no evidence that doing so favors tumor growth. Specific treatment depends on whether or not the patient is also being treated with chemotherapy.

Suggested Reading
Bateller L, Dalmau JO. Paraneoplastic disorders of the central nervous system: Update on diagnostic criteria and treatment. Semin Neurol 2004;24(4):461-471.

Dropcho EJ. Autoimmune central nervous system paraneoplastic disorders: Mechanisms, diagnosis, and therapeutic options. Ann Neurol 1995;37(Suppl 1):S102-S113.