Subacute, progressive neurological decline

The patient is a previously healthy 39-year-old male with past medical history significant for remote traumatic brain injury (1978) and well-controlled seizure disorder (2002) who recently presented to an outpatient neurology clinic following two months of a progressive neurological decline. His decline began following an unusual headache associated with diplopia, blurred vision, generalized weakness and slurred speech. These symptoms resolved after an hour; however, they were followed by a subacute decline with progressive inability to perform daily activities. Since onset of the headache, the patient experienced personality changes including social withdrawal and depression, and worsening falls, dysarthria, and dysphagia. In the clinic, he was noted to have a slow, shuffling gait, retropulsion, and marked hypophonia bordering on mutism. Following an unrevealing MRI, EEG, and LP, he was treated for possible early-onset Parkinson's disease with ropinirole and returned home. A short time later, however, the patient presented to The Johns Hopkins Hospital with a dramatic oculomotor disorder characterized by decreased and intrusive eye movements and dramatic bifrontal hypofunction including emotional incontinence, utilization behavior and perseveration. At the time of his admission, he continued to have bradykinesia, anarthria, and dysphagia. Further, he reported intermittent fevers (to 102°F) and diarrhea over the past few weeks.

Status post traumatic left frontal brain injury following a motor vehicle accident with ensuing coma (4 days) and resultant encephalomalacia, but no clear residual functional deficit (1978, age 13). Seizure disorder characterized by generalized tonic-clonic seizures, well-controlled with medications (2002).

Both parents and his brother and sister are alive and well. Both parents and both siblings have Crohns disease. In recent years, his father has experienced memory loss of unclear etiology, possibly due to Alzheimer's disease or vascular disease. His brother suffers from depression.

The patient is a college graduate, earning a Masters degree in Economics. Prior to the recent onset of his symptoms, he was a self-employed consultant and was a physically active marathon runner and cyclist. Although a functional member of society, his social interactions were reportedly awkward and possibly deviant, leading to job instability in the 1990s. Over the past two months, he experienced job instability related to his personality changes and neurologic decline. He denies use of alcohol, tobacco, and illicit drugs.

Valproic Acid 500 mg po BID, Ropinerole 0.25 mg po TID, Zaleplon 5 mg po qhs

No known drug allergies.

Intermittent mild to moderate fever. Diarrhea.

• Weight: 99 lbs Height: 5'2" T: 99.7 RR: 16 BP: 128/83 P: 100-110
• General: Thin, well-developed Caucasian male consistent with stated age. Anxious piercing gaze, despite a bland emotionless face.
• HEENT: Sclera anicteric. Clear oropharynx. No lymphadenopathy. Normal thyroid.
• CV: Regular rate and rhythm without murmur. No carotid bruits.
• Lungs: Clear to auscultation bilaterally. No rales or rhonchi.
• Abdomen: Soft, and nontender to palpation. Normoactive bowel sounds. No inguinal hernias or inguinal lymphadenopathy.
• Genitalia: Descended, non-tender testes, without palpable masses. Normal digital rectal exam.
• Extremities: No clubbing, cyanosis or edema.
• Skin: No rashes
• Neurologic Examination:
  • Mental State: Alert and oriented to person, date, and location.
  • Affect and behavior: Disinhibited, with emotional incontinence, perseveration, utilization behavior and a positive clapping sign.
  • Communication: Near mute, but able to communication at a sophisticated level via slow typing on a computer or hand motions (thumbs up - yes, thumbs down - no).
  • Comprehension: Able to follow multi-part commands and type sentences and paragraphs. Able to perform serial seven calculations.
  • Cranial Nerves II-XII: Static eyelid retraction and fluttering exacerbated by attempted eye movements. Reflex blepharospasm. Pupils equal and reactive to light. Incomplete mixed vertical and horizontal supranuclear gaze palsy with frequent intrusions. Intrusions included both back-to-back, low-amplitude saccades (multi-vectorial [vertical/torsional > horizontal]) and slow intrusions (mostly torsional). There were unusual nystagmoid movements on attempted convergence. Visual fields full to confrontation. Symmetric face. Midline tongue and uvula. No palatal myoclonus or adventitious jaw movements. Dysphagia including difficulty swallowing.
  • Motor Exam: Strength - 5/5 bilaterally. Tone - rigid without cogwheeling, most pronounced in the upper extremities. Coordination - largely intact but bradykinetic. Difficulty with rapid alternating movements. Gait - Small, slow, shuffling steps with a tendency to retropulse when standing with feet together (positive Romberg). Bulk, sensation and reflexes - within normal limits.

• Na 132; K 4.1; Cl 94; BUN 18; Cr 0.8; Glucose 87; Calcium 10.0; TP 7.8; Albumin 5.0; TBili 0.5; AST 21; ALT 36; Alk Phos 42
• WBC 8,750; RBC 4.58; Hemoglobin 14.8; Hct 41.0; MCV 89.5; Platelet 267
• PT 11.2; INR 1.0; APTT 28.9
• Vitamin B12 435; Vitamin B1 111; RBC folate 447; TSH 1.78; pyruvate 0.03; lactic acid 0.7, Ammonia 25, Magnesium 1.8
• RPR non-reactive, HIV negative, Lyme disease antibody negative
• SPEP and UPEP without evidence of a monoclonal gammopathy
• CSF (Lumbar Puncture): WBC 2 (mononuclear cells); RBC 520/0; glucose 56; protein 60; 14-3-3 protein <2.0; cryptoccocus antigen negative; PCR negative for Tropheryma Whipplei, EBV, CMV, VZV, HSV, and JC; culture negative for bacteria and fungi;
• PSA 0.2; AFP 15, CEA 4.1, hCG negative
• ESR 3; CRP 18.8; Negative ANA, anti-DNAse, Anti-Ro, Anti-La, and Rheumatoid Factor
• Heavy metal urine screen (arsenic, lead, and mercury) negative

• CT, head: Left greater than right encephalomalacia, consistent with prior trauma. Increased right frontal hypodensity compared to prior scan (two years prior).
• MRI, brain (Image 1): Serial axial fluid-attenuated inversion recovery (FLAIR) images show (A) bifrontal encephalomalacia indicating previous traumatic injury. In addition, there is increased signal intensity in the (B) bilateral globus palladi, (C) right greater than left substantia nigra, (D) hypothalamic regions adjacent to the inferior third ventricles, and a hyperintense lesion in the left temporal white matter. No associated mass effect or enhancement.
• CT, chest, abdomen and pelvis: Negative for occult tumor and lymphadenopathy.
• FDG-PET brain and body: No metabolic abnormality.

• Duodenal biopsy: Duodenal mucosa with non-diagnostic findings. Negative for T. whipplei by routine H&E stain, PAS stain and immunohistochemistry.
• Right Brain Biopsy: Histologically unremarkable dura and deep white matter. Cortical brain with vascular changes, including thickened vessels negative for amyloid on Congo red stain. No evidence of fungi (GMS), bacteria (Brown and Hopps) and acid fast organisms (AFB) by special stains. No evidence of prion protein, Herpes virus, adenovirus, papova virus, or T. whipplei by immunohistochemical stains.

• Electromyogram: Within normal limits.
• EEG: Posterior basic rhythm slowing, no seizure discharge or localizing signs.
• Fundoscopic exam with slit lamp biomicroscopy: No evidence of uveitis or vitreitis.

Despite a thorough work up for metabolic, autoimmune, neoplastic, and infectious etiologies, a definitive cause of the patient's symptoms was not identified. The patient began empiric treatment with intravenous Ceftriaxone and experienced a notable improvement of his eye movements with a decrease in intrusive eye movements, an improvement in his swallowing difficulties, and an improvement in his social interactions. His gait and speech, however, remained unchanged. Overall, his symptoms waxed and waned, and his response to Ceftriaxone was considered equivocal.

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